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Cold-Induced Sweating Syndrome Including Crisponi Syndrome

Synonym: CISS

, MD, FRCP(C) and , MD, PhD.

Author Information
, MD, FRCP(C)
Department of Clinical Neurological Sciences
London Health Sciences Centre
University of Western Ontario
London, Ontario, Canada
, MD, PhD
Center for Medical Genetics and Molecular Medicine
Haukland University Hospital
Bergen, Norway

Initial Posting: ; Last Update: July 18, 2013.

Summary

Disease characteristics. Crisponi syndrome, the infantile presentation of cold-induced sweating syndrome (CISS), is characterized by dysmorphic features (distinctive facies, lower facial weakness, flexion deformity at the elbows, camptodactyly with fisted hands, misshapen feet, and overriding toes), poor suck reflex and severely impaired swallowing, temperature spikes not associated with infections, and increased risk for seizures and sudden death. During the first decade of life, children with CISS develop profuse sweating of the face, arms, and chest with ambient temperatures below 18º to 22º C and often with other stimuli including apprehension or ingestion of sweets. Affected individuals sweat very little in hot environments and may feel overheated. In the second decade, progressive thoracolumbar kyphoscoliosis requires intervention.

Diagnosis/testing. The diagnosis of CISS/Crisponi syndrome is based on clinical findings and family history. Mutations in CRLF1 account for about 90% and mutations in CLCF1 account for about 10% of CISS and Crisponi syndrome.

Management. Treatment of manifestations: Infants with Crisponi syndrome require intervention for feeding difficulties, for episodes of respiratory distress with laryngospasm, and for bouts of hyperthermia, which may lead to seizures or sudden death. Bracing, occupational therapy, or plastic surgery may be necessary to correct congenital finger and hand deformities. Surgical intervention or prolonged bracing may be required to treat the progressive thoracolumbar kyphoscoliosis. Sweating triggered by cold or apprehension can be effectively treated with clonidine alone or combined with amitriptyline. Moxonidine may also be tried.

Agents/circumstances to avoid: Heat exposure and prolonged physical activity in hot climate.

Pregnancy management: Pharmacologic treatments for cold-induced sweating should be discontinued during pregnancy, as teratogenic effects on the fetus have not been well studied and remain a possibility.

Genetic counseling. Cold-induced sweating syndrome (CISS) and Crisponi syndrome are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If the disease-causing mutations have been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.

Diagnosis

Clinical Diagnosis

Diagnosis of cold-induced sweating syndrome (CISS) or its infantile presentation (Crisponi syndrome) requires the following cardinal clinical characteristics:

  • Dysmorphic features present at birth (Figure 1A, Figure 1B) including:
    • Rounded face, poorly developed and depressed nasal bridge, anteverted nares, and long philtrum
    • High-arched palate and micrognathia
    • Low-set ears
    • Cubitus valgus and flexion deformity at the elbows
    • Fisted hands, camptodactyly, overriding fingers, and transverse palmar creases
    • Misshapen feet and overriding toes
  • Characteristic facial expression (Figure 1A, Figure 2A) including:
    • Intermittent contracture of the facial muscles, puckering of the lips, and drooling of foamy saliva when crying or being handled
    • Normal facial expression when relaxed or sleeping (Figure 1B)
    • Typically, excessive startling and opisthotonus-like posturing with unexpected tactile stimuli (Figure 3)
  • Poor suck reflex and severely impaired swallowing present at birth
    • Marked difficulty feeding that may necessitate nasogastric or gastrostomy tube feeding
    • Mild lower facial weakness that usually persists throughout life (Figure 2B)
  • Scaly erythematous rash (Figure 2A)
    • Present in infancy and persisting throughout early childhood
    • Affects the face, fingers, and occasionally trunk
  • Paradoxical, cold-induced sweating with onset in the first decade
    • Profuse sweating on the face, arms, and anterior and posterior chest to the waist at environmental temperatures below 18º-22º C (64º-71º F)
    • Sweating also observed with nervousness and ingestion of sweets (illustrated in Hahn et al [2006])
  • Other thermoregulatory abnormalities
    • Minimal sweating (and limited to the lumbar region, groin, and thighs) in heat, resulting in uncomfortable overheating
    • Temperature spiking (41º C [106º F]) in infancy not associated with infections, leading in some cases to seizures and sudden death
  • Progressive thoracolumbar kyphoscoliosis requiring bracing or surgical intervention in the second decade
Figure 1

Figure

Figure 1.

A. Newborn with Crisponi syndrome (CISS1) showing camptodactyly with fisted hands and characteristic facial features (rounded face, poorly developed and depressed nasal bridge, anteverted nares, long philtrum, facial grimacing, (more...)

Figure 2

Figure

Figure 2.

A. 18-month-old girl with Crisponi syndrome (CISS2) demonstrating typical facial muscle contraction and puckering of the lips. Note the characteristic erythematous rash over the cheeks.

B. Younger sister to (more...)

Figure 3

Figure

Figure 3. Infant with Crisponi syndrome (CISS2) demonstrating the tendencies to grimace and to startle while being handled. The infant assumes an extensor posture, retracting the head and raising and flexing the arms.

Molecular Genetic Testing

Gene. Mutations in two genes are known to cause CISS:

  • CRLF1 (cytokine receptor-like factor 1), a class I cytokine receptor, represents the major locus for CISS (CISS1) [Knappskog et al 2003].
  • CLCF1 (cardiotrophin-like cytokine factor 1), a member of the glycoprotein (gp)130 cytokine family, represents the minor locus for CISS (CISS2) [Hahn et al 2006].

All individuals with CISS have been found to have mutations in one of these two genes.

Table 1. Summary of Molecular Genetic Testing Used in Cold-Induced Sweating Syndrome including Crisponi Syndrome (CISS)

Gene 1Proportion of CISS Attributed to Mutations in This GeneTest Method 2Mutations Detected
CRLF1~90%Sequence analysis 3Sequence variants
Deletion/duplication analysis 4Exonic or whole-gene deletions 5
CLCF1~10%Sequence analysis 3Sequence variants 6, 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. One large deletion involving parts of CRLF1 has been reported [Di Leo et al 2010]. See Table 2.

6. Only three individuals (including two sisters) with CISS2 have been reported, all are compound heterozygous.

7. See Table 3.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Clinical evaluation
    • The clinical presentation in the neonatal period is characteristic, with few differential diagnostic considerations.
    • Family history may reveal presumably affected siblings who had died in infancy without a satisfactory diagnosis.
    • In adult probands, baby photographs and clinical information may reveal the findings of Crisponi syndrome, the infantile manifestation of CISS.
  • Molecular genetic testing
    • Sequencing of CRLF1 and CLCF1 (in that order) is likely to identify mutations on both alleles and therefore provide molecular confirmation of CISS in most individuals with typical clinical findings.
    • Although large exonic/whole-gene deletions are rare, apparent heterozygosity for a single pathogenic mutation in either CRLF1 or CLCF1 identified by sequence analysis in an individual with classic features of the disorder strongly indicates compound heterozygosity for a second unidentified mutation and warrants deletion analysis. See Table 1, footnote 4 for methods.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Cold-induced sweating syndrome (CISS) can present to the clinician in infancy as Crisponi syndrome or as cold-induced sweating from age three years onwards [Sohar et al 1978, Hahn et al 2006, Crisponi et al 2007, Hahn et al 2010]. Interviews with mothers of children or adults with CISS revealed that probably all had had findings of Crisponi syndrome in infancy, some more severe than others [Hahn et al 2010].

Presentation in Infancy (Crisponi Syndrome)

Typical craniofacial and skeletal dysmorphic features (see Clinical Diagnosis) are noted at birth and are accompanied by an inability to suckle and swallow as a result of facial and bulbar weakness. When crying or being handled, infants tend to startle excessively; they transiently assume an opisthotonus-like posture with the arms flexed with fisted hands, and show characteristic facial contractions with tightly pursed lips and excessive salivation.

Life-threatening respiratory difficulties and unexplained high fevers (≤42º C [108º F]) can lead to seizures and sudden death. Crisponi [1996] originally described this presentation in 17 newborns from 12 families of southern Sardinia. As 15 of the infants died in the first few months, the condition was considered to have a poor prognosis. However, it is now recognized that survival past infancy can be expected since most early infantile problems disappear gradually over the first two years of life.

Usually affected infants begin to feed normally by age one to two years. Occasionally, dysphagia persists throughout the first decade and may be associated with disinterest in food or liquids. Excessive startling disappears by age two years. Psychomotor development is usually normal [Hahn et al 2010].

Presentation in Childhood and Adulthood

Cold-induced sweating, the most disabling symptom in adulthood, is recognized during the first decade (age ≥3 years). With environmental temperatures of 22°C (72º F) or lower, affected individuals sweat profusely on their face and upper body, accompanied by intense shivering and dermal vasoconstriction, so that the fingers appear cold and cyanosed. Profuse sweating is also triggered by apprehension, nervousness, or by sweet gustatory stimuli, in particular by chocolate. In contrast, affected individuals sweat very little in heat and only in the lumbar region, the groin, and the anterior thigh. They become flushed and unpleasantly overheated in hot climates [Hahn et al 2006, Hahn et al 2010]. Although the hyperhidrosis can be effectively treated [Hahn et al 2006, Hahn et al 2010, Herholz et al 2010], heat intolerance is a lifelong problem.

Towards the end of the first decade, affected children develop a progressive thoracolumbar kyphoscoliosis that requires either bracing or spinal instrumentation.

Once the difficulties of early childhood have been overcome, individuals with CISS/Crisponi syndrome are, for the most part, able to lead a fairly normal and productive life, obtain a secondary education, and have children. Life expectancy is probably normal; to date only one individual has been followed to the eighth decade [Hahn et al 2006].

Other Findings

Laboratory tests, metabolic studies, and detailed studies of autonomic functions are usually normal [Hahn et al 2006].

EMG and nerve conduction velocity are generally normal. Decrease in the perception of light touch and painful stimuli and atrophy of small foot muscles have rarely been observed, indicating a mild chronic axonal sensory and motor peripheral neuropathy. In this instance motor and sensory nerve conduction velocities recorded from sural nerves and from peroneal nerves were normal, but the evoked sensory and motor action potential amplitudes were reduced.

Clinical observation has suggested that some individuals with CISS have decreased pain perception; the following additional tests could be performed to explore further the possibility of impaired development of sensory neurons:

  • Quantitative sensory testing (QSART)
  • Nerve biopsies with morphometric analyses and ultrastructural evaluation
  • Skin biopsy with quantitative analysis of sensory innervation

Genotype-Phenotype Correlations

Clinical manifestations are stereotypic and seemingly identical whether CRLF1 or CLCF1 is mutated [Hahn et al 2010]. However, only three affected individuals with CLCF1 mutations from two families have so far been reported [Hahn et al 2006, Hahn et al 2010].

Variation in clinical severity associated with different mutations has not been reported.

Nomenclature

The term “cold-induced sweating syndrome” was coined [Knappskog et al 2003] from the title of the Lancet report “cold-induced profuse sweating on back and chest” [Sohar et al 1978].

Following the demonstration of locus heterogeneity, the abbreviations CISS1 and CISS2 were introduced [Hahn et al 2006]. As CISS1 and CISS2 are clinically indistinguishable, the term “CISS” covers both disorders until a molecular diagnosis is made.

Survivors of infantile-onset Crisponi syndrome [Crisponi 1996] with time will develop CISS, substantiated by the demonstration of causative mutations in CRLF1 [Crisponi et al 2007, Dagoneau et al 2007] and in CLCF1 [Hahn et al 2010]. Thus, CISS and Crisponi syndrome are not “allelic disorders” [Crisponi et al 2007], but rather Crisponi syndrome is the infantile presentation of CISS [Hahn et al 2010].

Prevalence

CISS1 (caused by mutations in CRLF1) appears to be more frequent than CISS2 (caused by mutations in CLCF1).

CISS1 has so far been observed in individuals originating from Europe, the Middle East, India, East Asia, and North America [Knappskog et al 2003, Hahn et al 2006, Crisponi et al 2007, Dagoneau et al 2007, Okur et al 2008, Thomas et al 2008, Tüysüz et al 2009, Di Leo et al 2010, Hahn et al 2010, Yamazaki et al 2010, Cosar et al 2011, Herholz et al 2011, Dessi et al 2012, Hakan et al 2012]. CISS1 seems to be particularly prevalent in the Mediterranean region [Crisponi 1996, Crisponi et al 2007, Dagoneau et al 2007].

To date only three individuals with CISS2 have been reported [Hahn et al 2006, Hahn et al 2010].

Differential Diagnosis

Stüve-Wiedemann syndrome (STWS). In the infantile period, the Stüve-Wiedemann syndrome (STWS) (OMIM 601559), caused by mutations in LIFR encoding leukemia inhibitory factor receptor [Dagoneau et al 2004], shares clinical features with CISS [Jung et al 2010]. Although chondrodysplasia (manifest as congenital bowing of the long bones and decreased joint mobility) is the main characteristic of STWS, other findings include camptodactyly; severe sucking, swallowing, and feeding difficulties; episodic respiratory distress; episodes of hyperthermia; and sudden death. Few individuals with STWS who have survived the first year show persistent thermoregulatory difficulties and abnormal sweating [Gaspar et al 2008]. Cold-induced sweating (called paradoxical sweating) was reported in two unrelated individuals [Di Rocco et al 2003]. In their teens survivors may manifest dental decay and progressive kyphoscoliosis [Jung et al 2010].

Jung et al [2010] reported several individuals with a typical STWS phenotype who did not have mutations in LIFR or in CRLF1. Genetic heterogeneity for STWS is suggested.

Distal arthrogryposis type 2A and distal arthrogryposis type 2B. The intermittent facial muscle contraction and puckering of the lips of young children with Crisponi syndrome may bear some resemblance to distal arthrogryposis type 2A (Freeman-Sheldon syndrome; OMIM 193700), caused by mutation of MYH3 and to distal arthrogryposis type 2B (Sheldon-Hall syndrome; OMIM 601680), some of which may be caused by mutation in MYH3. However, puckering of the lips that gives this appearance is not evident in infants or older children when they are relaxed. While camptodactyly is a shared feature, microstomia is not present in Crisponi syndrome.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with cold-induced sweating syndrome (CISS/Crisponi syndrome), the following evaluations are recommended:

  • Brain MRI. Usually normal, but may be done to evaluate for complicating features including a thin corpus callosum [Okur et al 2008] or small subcortical white matter lesions [Yamazaki et al 2010].
  • Swallowing tests and esophageal manometry. May be helpful in assessing the safety of oral feeding.
  • EEG when seizures are observed or suspected
  • Medical genetics consultation

Treatment of Manifestations

Infants require close monitoring in anticipation of episodes of laryngospasm with respiratory distress, bouts of hyperthermia (≤42º C), seizures, and possible sudden death. Preparedness for appropriate countermeasures (e.g., supplemental oxygen, cooling blankets, antiepileptic drugs) is essential.

An apnea monitor is recommended.

Serial or continuous electroencephalogram (EEG) monitoring may be required during the first few weeks if seizures are observed. Anticonvulsants may be required.

To overcome precarious feeding problems, infants need prolonged nasogastric or gastrostomy tube feeding for one year or longer.

Bracing, occupational therapy, or plastic surgery may be necessary to correct congenital finger and hand deformities.

Surgical instrumentation or prolonged bracing may be required to correct a progressive thoracolumbar scoliosis.

Paradoxical sweating. Treatment should be reserved for adult patients and older children. The combined prescription of clonidine and amitriptyline can provide excellent and long-term symptom control.

  • Clonidine. Episodes of cold-induced sweating are associated with a prominent increase in plasma noradrenaline. Clonidine, a central presynaptic α2-adrenoreceptor agonist, induces feedback inhibition of synaptic noradrenaline release. Oral Clonidine, at starting doses of 0.05 mg to 0.1 mg twice daily, effectively reduces cold-induced sweating and is usually well tolerated. If there are no contraindications, the drug is maintained at the lowest dose required for acceptable symptom control.
    • Before initiating a prescription of clonidine, check potential interactions with already prescribed medications
    • The beneficial effects of clonidine may lessen within a few weeks of starting the drug, due to habituation.
    • A gradual increase in the daily dose of clonidine to tolerance (side effects: dry mouth, postural hypotension, sedation) or to a maximum of 0.1 mg four times daily may be required.
    • If clonidine needs to be discontinued, the prescription should be phased out over four to six days; abrupt cessation of clonidine can lead to prominent hypertension.
  • Amitriptyline. Amitriptyline10 mg orally at bedtime may be added to the prescription of clonidine when symptoms are not adequately controlled. The dose may need to be increased gradually to a maximum of 25 mg four times daily (taken together with clonidine).
  • Moxonidine, prescribed at a maximum oral dose of 6 μg/kg/d, was shown to provide effective symptom relief in two teenage siblings with CISS [Herholz et al 2010]. In short-term prescription, moxonidine was well tolerated; however, long-term observations are not yet available.

Prevention of Primary Manifestations

See Treatment of Manifestations.

Surveillance

Surveillance includes monitoring for evidence of scoliosis and its progression.

Agents/Circumstances to Avoid

Affected individuals should avoid heat exposure and prolonged physical activity in a hot climate.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Females affected with CISS1 or CISS2 may conceive normally. No complications during pregnancy have so far been reported. Treatments for cold-induced sweating (clonidine, amitriptyline, monoxidine) should be discontinued during pregnancy, as the potential for teratogenic effects on the fetus is not well studied and remains possible. The prescription of clonidine should not be discontinued abruptly; the drug should be phased out over four to six days.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Cold-induced sweating syndrome (CISS) and Crisponi syndrome are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with CISS are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

If the disease-causing mutations in the family have been identified, carrier testing for at-risk family members is possible through laboratories offering either testing for the gene of interest or custom testing.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations have been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.

Fetal ultrasound examination. In populations with documented CRLF1 founder mutations and an increased prevalence of CISS1, a prenatal diagnosis of CISS may be suspected when evidence of camptodactyly is identified [Dessi et al 2012].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for Cold-Induced Sweating Syndrome including Crisponi Syndrome have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Cold-Induced Sweating Syndrome including Crisponi Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Cold-Induced Sweating Syndrome including Crisponi Syndrome (View All in OMIM)

272430COLD-INDUCED SWEATING SYNDROME 1; CISS1
604237CYTOKINE RECEPTOR-LIKE FACTOR 1; CRLF1
607672CARDIOTROPHIN-LIKE CYTOKINE FACTOR 1; CLCF1
610313COLD-INDUCED SWEATING SYNDROME 2; CISS2

Molecular Genetic Pathogenesis

The ciliary neurotrophic factor receptor (CNTFR) pathway supports the differentiation and survival of a wide range of neural cell types during development and in adulthood. Cytokine receptor-like factor 1 (CRLF1) and cardiotrophin-like cytokine factor 1 (CLCF1) are soluble cytokines that form a stable heterodimeric complex CRLF1/CLCF1, which acts as a second functional ligand to CNTFR. Binding of CLCF1 to CNTFRα results in the recruitment and dimerization of glycoprotein 130 (gp130) and leukemia inhibitory receptor (LIFR). In turn, this induces downstream signaling events and the activation of the JAK1-STAT3 signaling pathway [Heinrich et al 2003].

The CNTFR pathway plays an essential role during the embryonic development of motor neurons. Mice lacking a functional CNTFRα exhibit profound motor neuron deficits and die shortly after birth, while mice and humans deficient of CNTF, the primary ligand to CNTFRα, are healthy [Takahashi et al 1994, DeChiara et al 1995]. Moreover, targeted deletions of the murine orthologs of the human CLCF1, CRLF1, CNTFR, or LIFR genes were associated with a severe reduction in facial and lumbar motor neurons. The newborn mice had decreased facial mobility: they did not suckle and died shortly after birth [Li et al 1995, Forger et al 2003, Zou et al 2009]. The findings are analogous to those of infants with CISS/Crisponi syndrome who suffer from severe oral-facial weakness, impaired suckling and swallowing, and complete disinterest in food and drink. The observations illustrate the importance of the CNTFR/gp130/LIFR tripartite receptor and its ligand CLCF1 for the embryonic development of facial motor neurons.

Early on, infants with CISS tend to startle excessively. When crying or being handled, they assume a transient opisthotonus-like posture; their faces become contracted in a trismus-like fashion, the lips pursed and extruding ample saliva; they also develop laryngospasm, difficulty breathing, and circumoral cyanosis as a sign of anoxia. These episodes resemble hereditary hyperekplexia, which is caused by impaired glycine inhibition in the brain stem and spinal cord [Shiang et al 1993, Davies et al 2010]. Despite the clinical similarities, it is presently not known whether there is a shared pathophysiology. Crisponi [1996] found low levels of gamma-amino butyric acid (GABA) in cerebrospinal fluid in a single affected infant and, therefore, considered the possibility of impaired GABA inhibition in Crisponi syndrome. The observation has not been confirmed.

During the first year, infants with CISS spike fevers (42º C) without signs of infections; they may suffer convulsions and even die suddenly. Such episodes are also observed in Stüve-Wiedemann syndrome (STWS), a closely related disorder caused by null mutations in LIFR [Dagoneau et al 2004]. The basis for episodic hyperthermia is presently not known. In both CISS and STWS, affected individuals display lifelong heat intolerance and impaired thermoregulation due to their limited ability to sweat in heat [Jung et al 2010]. Early-onset cold-induced sweating was reported in the two individuals with STWS who had survived infancy [Di Rocco et al 2003]. These observations indicate that both components of the gp130/LIFR signal transducers are required for cholinergic differentiation of sympathetic neurons that innervate mature sweat glands [Stanke et al 2006].

From childhood onwards, the most disabling symptoms for persons with CISS stem from their abnormalities of sweating, while all other autonomic functions are intact [Hahn et al 2006]. Sometime during the first decade (age ≥3 years), affected individuals exhibit a characteristic hyperhidrosis involving the face and upper body when they are exposed to low environmental temperatures or when nervous or anxious. Paradoxically, they sweat very little in heat and only in the lumbar region, the groin and thighs [Hahn et al 2006]. Thus, they feel uncomfortably overheated in hot weather.

Sweating is controlled by the sympathetic nervous system, whereby mature eccrine sweat glands are innervated by cholinergic postganglionic sympathetic neurons. Yet, in development and before sweat glands assume their secretory functions, the innervating sympathetic neurons express a noradrenergic phenotype. This switch in transmitter phenotype of sympathetic neurons is induced by a soluble retrograde signal that is secreted by the sweat glands as they become active after birth [Habecker et al 1997, Francis & Landis 1999]. This target-derived signal was shown to mediate cholinergic differentiation of sympathetic neurons via the gp130/LIFR pathway [Stanke et al 2006]. Although the molecular identity of the cholinergic differentiation factor remains to be defined, the CRLF1/CLCF1 cytokines are possible candidates as they are expressed on the surface of developing sweat glands [Stanke et al 2006].

At birth, individuals with Crisponi syndrome manifest stereotypic cranial and skeletal dysmorphic features as well as joint and digital abnormalities. Moreover, towards the end of the first decade, they predictably develop progressive thoracolumbar scoliosis that often requires spinal instrumentation. The precise pathomechanisms need further study.

CRLF1/CLCF1 soluble cytokines belong to the IL6 family of cytokines, which share a common signal transducer gp130/ LIFR and play a role in bone formation during development and in the ongoing remodeling of endochondral bone [Sims & Walsh 2010]. The cytokines enhance the differentiation of osteoblasts and modulate their function, thereby shifting the balance of remodeling toward bone formation [Heymann & Rousselle 2000, Blanchard et al 2009, Soltanoff et al 2009, Yang 2009]. Periosteum, the connective tissue surrounding bone, plays an important role in bone development. Periosteum is innervated by postganglionic sympathetic neurons of thoracic sympathetic ganglia, which initially display noradrenergic properties, but postnatally assume a cholinergic neurotransmitter phenotype similar to the sympathetic neurons innervating sweat glands [Asmus et al 2000]. This switch in neurotransmitter phenotype is induced by a retrograde soluble signal derived from periosteum and was shown to act via gp130/LIFR [Asmus et al 2001]. The target-derived factor belongs to the neuropoietic cytokine family of which LIF, CTNF, and CT-I have been ruled out, leaving CRLF1/CLCF1 as possible candidates [Habecker et al 1995, Habecker et al 1997, Asmus et al 2001].

In one individual with CISS2 the authors have shown that the identified CLCF1 mutations abrogate CLCF1 binding to CNTFRα, thereby resulting in failure of gp130/LIFR activation and STAT3 signaling [Rousseau et al 2006]. CLCF1 mutations presently identified in CISS2 patients are predicted to result in non-functional CLCF1 [Hahn et al 2010, Table 3]. The functional consequences of observed CRLF1 mutations of reported CISS1 patients are predicted to mostly result in nonfunctional CRLF1 [Knappskog et al 2003, Hahn et al 2006, Crisponi et al 2007, Dagoneau et al 2007, Di Leo et al 2010, Hahn et al 2010, Herholz et al 2011, Table 2]. Thus, it would seem plausible that the loss of function in one component of the CRLF1/CLCF1 complex leads to lack of activation of CNTFRα/gp130/LIFR and thereby in failure of downstream STAT3 signaling.

Target-dependent cholinergic differentiation of sympathetic neurons that innervate mature sweat glands was shown to be dependent on gp130 signaling [Stanke et al 2006]. Biopsies of skin, taken from an individual with CISS1and derived from an area of hyperhidrosis, illustrated that the sweat glands lacked cholinergic innervation, whereas the adrenergic supply was amply maintained [Di Leo et al 2010]. These observations require further study. If upheld, the findings would indirectly support a potential role for CLCF1/CRLF1 in the switch from noradrenergic to cholinergic phenotype of the sympathetic neurons innervating mature sweat glands.

CRLF1

Gene structure. CRLF1, also known as CLF, CLF-1, has nine exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. The Israeli sisters described by Sohar et al [1978] were homozygous for two novel syntenic (i.e., on the same allele) sequence variants (c.242G>A and c.1121T>G) [Knappskog et al 2003]. The family belonged to an ethnic minority. Their parents shared a common grandfather. None of the variants were found in a limited number of control samples from the same population. Computer prediction programs indicate that c.242G>A may be a tolerated variant whereas the c.1121T>G is probably pathogenic. It is thus possible that c.242G>A in the future may be encountered as a sequence variant not related to CISS in some populations.

Pathogenic allelic variants. CRLF1 mutations include missense, nonsense, splicing, and frameshift mutations resulting from small intragenic insertions, deletions, and indels. Larger deletions have also been reported (see Table 1).

Table 2. Selected CRLF1 Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Benignc.242G>A 1p.Arg81His 1NM_004750​.4
NP_004741​.1
c.73_75delCTGp.Leu26del
Pathogenicc.538C>Tp.Gln180Ter
c.852G>Tp.Trp284Cys
c.1121T>Gp.Leu374Arg
c.844_845delGTp.Val282fsTer47
c.31_53del23p.Gln11ValfsTer68
c.413C>Tp.Pro138Leu
c.303delCp.Asn102ThrfsTer47
c.397+1G>Ap.? 2
c.935G>Ap.Arg312His
Exon 6-9 deleted 3 p.? 2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Unknown variant, found syntenic with a likely pathogenic variant (p.Leu374Arg). See CRLF1, Benign allelic variants.

2. Protein has not been analyzed; an effect is expected but difficult to predict.

3. Described by Di Leo et al [2010]

Normal gene product. The first 37 amino acid residues of CRLF1 represent a signal peptide (UniProt O75462). This sequence contains five adjacent leucines (reference sequence NM_004750.4). In the Norwegian population, a variant with four leucines is commonly observed, seemingly in genetic equilibrium (29 heterozygotes and 2 homozygotes among 93 blood donors, allele frequency 0.18) [Hahn et al 2006].

Abnormal gene product. See Molecular Genetic Pathogenesis.

CLCF1

Gene structure. The NM_013246.2 reference sequence encodes the longer isoform #1 and has four exons; also known as CLC, BSF-3. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Only four putative causative variants in two families are published. Multiexonic or whole-gene deletions involving CLCF1 have not been described.

Table 3. Selected CLCF1 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.46T>Cp.Cys16ArgNM_013246​.2
NP_037378​.1
c.321C>Ap.Tyr107Ter
c.590G>Tp.Arg197Leu
c.676T>Cp.Ter226ArgextTer170 1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).

1. A nonstop mutation where the stop codon Ter226 has changed to an Arg adding a tail of 169 new amino acids after which a new stop codon (Ter170) is reached

Normal gene product. Though the NP_037378.1 isoform has a predicted signal peptide at amino acids 1-27, experiments show it to be retained within the cell. See Molecular Genetic Pathogenesis.

Abnormal gene product. See Molecular Genetic Pathogenesis.

References

Literature Cited

  1. Asmus SE, Parsons S, Landis SC. Developmental changes in the transmitter properties of sympathetic neurons that innervate periosteum. J Neurosci. 2000;20:1495–504. [PubMed: 10662839]
  2. Asmus SE, Tian H, Landis SC. Induction of cholinergic function in cultured sympathetic neurons by periostal cells: cellular mechanisms. Dev Biol. 2001;235:1–11. [PubMed: 11412023]
  3. Blanchard F, Duplomb L, Baud’huin M, Brounais B. The dual role of Il-6-type cytokines on bone remodeling and bone tumors. Cytokine Growth Factor Rev. 2009;20:19–28. [PubMed: 19038573]
  4. Cosar H, Kahramaner Z, Erdemir A, Turkoglu E, Kanik A, Sutcuoglu S, Onay H, Alpman A, Okinay F. Homozygous mutation of CRLF-1 gene in a Turkish newborn with Crisponi syndrome. Clin Dysmorphol. 2011;20:187–9. [PubMed: 21691203]
  5. Crisponi G. Autosomal recessive disorder with muscle contractions resembling neonatal tetanus, characteristic face, camptodactyly, hyperthermia, and sudden death: A new syndrome. Am J Med Genet. 1996;62:365–71. [PubMed: 8723066]
  6. Crisponi L, Crisponi G, Meloni A, Toliat MR, Nürnberg G, Usula G, Uda M, Masala M, Höhne W, Becker C, Marongiu M, Chiappe F, Kleta R, Rauch A, Wollnik B, Strasser F, Reese T, Jakobs C, Kurlemann G, Cao A, Nürnberg P, Rutsch F. Crisponi syndrome is caused by mutations in the CRLF1 gene and is allelic to Cold-induced sweating syndrome type 1. Am J Hum Genet. 2007;80:971–81. [PMC free article: PMC1852730] [PubMed: 17436252]
  7. Dagoneau N, Bellais S, Blanchet P, Sarda P, Al-Gazali LI, Di Roco M, Huber C, Djouadi F, Le Goff C, Munnich A, Cormier-Daire V. Mutations in cytokine receptor-like factor 1 (CRLF1) account for both Crisponi and Cold-induced sweating syndromes. Am J Hum Genet. 2007;80:966–70. [PMC free article: PMC1852726] [PubMed: 17436251]
  8. Dagoneau N, Scheffer D, Huber C, Al-Gazali LI, Di Rocco M, Godard A, Martinovic J, Raas-Rothschild A, Sigaudy S, Unger S, Nicole S, Fontaine B, Taupin J-L, Moreau J-F, Superti-Furga A, Le Merrer M, Bonaventure J, Munnich A, Legeai-Mallet L, Cormier-Daire V. Null leukemia inhibitory factor receptor (LIFR) mutations in Stüve-Wiedemann/Schwartz-Jampel Type 2 syndrome. Am J Hum Genet. 2004;74:298–305. [PMC free article: PMC1181927] [PubMed: 14740318]
  9. Davies JS, Chung S-K, Thomas RH, Robinson A, Hammond CL, Mullins JGL, Carta E, Pearce BR, Harvey K, Harvey RJ, Rees MI. The glycinergic system in human startle disease: a genetic screening approach. Front Mol Neurosci. 2010;3:1–10. [PMC free article: PMC2854534] [PubMed: 20407582]
  10. DeChiara TM, Vesjsada R, Poueymirou WT, Acheson A, Suri C, Conover JC, Friedman B, McClain J, Pan L, Stahl N, Ip NY, Yancopoulos GD. Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth. Cell. 1995;83:313–22. [PubMed: 7585948]
  11. Dessi A, Fanos V, Crisponi G, Frau A, Ottonello G. Isolated 'sign of the horns': a simple, pathognomonic, prenatal sonographic marker of Crisponi syndrome. J Obstet Gynaecol Res. 2012;38:582–5. [PubMed: 22381110]
  12. Di Leo R, Nolano M, Boman H, Pierangeli G, Provitera V, Knappskog PM, Cortelli P, Vita G, Rodolico C. Central and peripheral autonomic failure in cold-induced sweating syndrome type 1. Neurology. 2010;75:1567–9. [PubMed: 20975058]
  13. Di Rocco M, Stella G, Bruno C, Doria Lambda L, Bado M, Superti-Furga A. Long-term survival in Stuve-Wiedemann syndrome: a neuro-myo-skeletal disorder with manifestations of dysautonomia. Am J Med Genet A. 2003;118A:362–8. [PubMed: 12687669]
  14. Forger NG, Prevette D, deLapeyrière O, de Bovis B, Wang S, Bartlett P, Oppenheim RW. Cardiotrophin-like cytokine/cytokine-like factor 1 is an essential trophic factor for lumbar and facial motoneurons in vivo. J Neurosci. 2003;23:8854–8. [PubMed: 14523086]
  15. Francis NJ, Landis SC. Cellular and molecular determinants of sympathetic neuron development. Annu Rev Neurosci. 1999;22:541–66. [PubMed: 10202548]
  16. Gaspar IM, Saldanha T, Cabral P, Vilhena MM, Costa C, Dagoneau N, Daire VC, Hennekam RC. Long-term follow-up in Stuve-Wiedemann syndrome: a clinical report. Am J Med Genet A. 2008;146A:1748–53. [PubMed: 18546280]
  17. Habecker BA, Pennica D, Landis SC. Cardiotrophin-1 is not the sweat gland-derived differentiation factor. Neuroreport. 1995;7:41–4. [PubMed: 8742412]
  18. Habecker BA, Symes A, Stahl N, Francis NJ, Economides A, Fink J, Yancopoulos GD, Landis SC. A sweat gland-derived differentiation activity acts through known cytokine signaling pathways. J Biol Chem. 1997;272:30421–28. [PubMed: 9374533]
  19. Hahn AF, Jones DL, Knappskog PM, Boman H, McLoed JG. Cold-induced sweating syndrome. A report of two cases and demonstration of genetic heterogeneity. J Neurol Sci. 2006;250:62–70. [PubMed: 16952376]
  20. Hahn AF, Waaler PE, Kvistad PH, Bamforth JS, Miles JH, McLeod JG, Knappskog PM, Boman H. Cold-induced sweating syndrome:CISS1 and CISS2. Manifestations from infancy to adulthood. Four new cases. J Neurol Sci. 2010;293:68–75. [PubMed: 20400119]
  21. Hakan N, Eminoglu FT, Aydin M, Zenciroglu A, Karadag NN, Dursun A, Okumus N, Ceylaner S. Novel CRLF1 gene mutation in a newborn infant diagnosed with Crisponi syndrome. Congenit Anom (Kyoto). 2012;52:216–8. [PubMed: 23181498]
  22. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003;374:1–20. [PMC free article: PMC1223585] [PubMed: 12773095]
  23. Herholz J, Crisponi L, Mallick BN, Rutsch F. Successful treatment of cold-induced sweating in Crisponi syndrome and its possible mechanism of action. Dev Med Child Neurol. 2010;52:494–7. [PubMed: 20187881]
  24. Herholz J, Meloni A, Marongiu M, Chiappe F, Deiana M, Herrero CR, Zampino G, Hamamy H, Zalloum Y, Waaler PE, Crisponi G, Crisponi L, Rutsch F. Differential secretion of the mutated protein is a major component affecting phenotypic severity in CRLF1-associated disorders. Eur J Hum Genet. 2011;19:525–33. [PMC free article: PMC3083629] [PubMed: 21326283]
  25. Heymann D, Rousselle A-V. gp130 cytokine family and bone cells. Review article. Cytokine. 2000;12:1455–68. [PubMed: 11023660]
  26. Jung C, Dagoneau N, Baujat G, Le Merrer M, David A, Di Rocco M, Hamel B, Mégarbané A, Superti-Furga A, Unger A, Munnich A, Cormier-Daire V. Stüve-Wiedemann syndrome: long-term follow-up and genetic heterogeneity. Clin Genet. 2010;77:266–72. [PubMed: 20447141]
  27. Knappskog PM, Majewski J, Livneh A, Nilsen PTE, Bringsli JS, Ott J, Boman H. Cold-induced sweating syndrome is caused by mutations in the CRLF1 gene. Am J Hum Genet. 2003;72:375–83. [PMC free article: PMC379230] [PubMed: 12509788]
  28. Li M, Sendtner M, Smith A. Essential function of LIF receptor in motor neurons. Nature. 1995;378:724–7. [PubMed: 7501019]
  29. Okur I, Tumer L, Crisponi L, Eminoglu FT, Chiappe F, Cinaz P, Yenicesu I, Hasanoglu A. Crisponi syndrome: A new case with additional features and new mutation in CRLF1. Am J Med Genet A. 2008;146A:3237–9. [PubMed: 19012339]
  30. Rousseau F, Gauchat J-F, McLeod JG, Chevalier S, Guillet C, Guilhot F, Cognet I, Froger J, Hahn AF, Knappskog PM, Gascan H, Boman H. Inactivation of cardiotrophin-like cytokine, a second ligand for ciliary neurotrophic factor receptor, leads to cold-induced sweating syndrome in a patient. Proc Natl Acad Sci U S A. 2006;103:10068–73. [PMC free article: PMC1502507] [PubMed: 16782820]
  31. Shiang R, Ryan SG, Zhu YZ, Hahn AF, O’Connell P, Wasmuth JJ. Mutations in the α1 subunit of the inhibitory glycine receptor cause the dominant neurological disorder, hyperekplexia. Nat Genet. 1993;5:351–8. [PubMed: 8298642]
  32. Sims NA, Walsh NC. GP130 cytokines and bone remodelling in health and disease. BMB Rep. 2010;43:513–23. [PubMed: 20797312]
  33. Sohar E, Shoenfeld Y, Udassin R, Magazanik A, Revach M. Cold-induced profuse sweating on back and chest. A new genetic entity? Lancet. 1978;2:1073–4. [PubMed: 82089]
  34. Soltanoff CS, Chen W, Yang S, Li Y-P. Signalling networks that control the lineage commitment and differentiation of bone cells. Crit Rev Eukaryot Gene Expr. 2009;19:1–46. [PMC free article: PMC3392028] [PubMed: 19191755]
  35. Stanke M, Duong CV, Pape M, Geissen M, Burbach G, Deller T, Gascan H, Parlato R. Target-dependent specification of the neuro-transmitter phenotype: cholinergic differentiation of sympathetic neurons is mediated in vivo by gp130 signaling. Development. 2006;133:141–50. [PubMed: 16319110]
  36. Takahashi R, Yokoji H, Misawa H, Hayashi M, Hu J, Deguchi T. A null mutation in the human CNTF gene is not causally related to neurological diseases. Nat Genet. 1994;7:79–84. [PubMed: 8075647]
  37. Thomas N, Danda S, Kumar M, Jana AK, Crisponi G, Meloni A, Crisponi L. Crisponi syndrome in an Indian patient: a rare differential diagnosis for neonatal tetanus. Am J Med Genet A. 2008;146A(283):1–4. [PubMed: 18837055]
  38. Tüysüz B, Yeşil G, Kasapçopur O, Knappskog PM, Boman H. Two Turkish brothers with cold-induced sweating syndrome caused by a novel missense mutation in the CRLF1 gene. Poster session. Abstract 2591/F/Poster Board #107. Honolulu, Hawaii: American Society of Human Genetics 59th Annual Meeting; 2009. Available online. Accessed 6-23-14.
  39. Yamazaki M, Kosho T, Kawachi S, Mikoshiba M, Takahashi J, Sano R, Oka K, Yoshida K, Watanabe T, Kato H, Komatsu M, Kawamura R, Wakui K, Knappskog PM, Boman H, Fukushima Y. Cold-induced sweating syndrome with neonatal features of Crisponi syndrome: Longitudinal observation of a patient homozygous for a CRLF1 mutation. Am J Med Genet A. 2010;152A:764–9. [PubMed: 20186812]
  40. Yang Y. Skeletal morphogenesis during embryonic development. Crit Rev Eukaryot Gene Expr. 2009;19:197–218. [PubMed: 19883365]
  41. Zou X, Bolon B, Pretorius JK, Kurahara C, McCabe J, Christiansen KA, Sun N, Duryea D, Foreman O, Senaldi G, Itano AA, Siu G. Neonatal death in mice lacking cardiotrophin-like cytokine is associated with multifocal neuronal hypoplasia. Vet Pathol. 2009;46:514–9. [PubMed: 19098279]

Chapter Notes

Revision History

  • 18 July 2013 (me) Comprehensive update posted live
  • 3 March 2011 (me) Review posted live
  • 1 June 2010 (hb) Original submission
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