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Cold-Induced Sweating Syndrome Including Crisponi Syndrome

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

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

Initial Posting: ; Last Update: March 17, 2016.

Summary

Clinical 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, and temperature spikes associated with an 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 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 established by clinical findings or, if clinical findings are insufficient, by identification of biallelic pathogenic variants in CRLF1 or CLCF1.

Management.

Treatment of manifestations: Infants with Crisponi syndrome require close monitoring for risk of laryngospasm with respiratory distress and for bouts of hyperthermia, which may lead to seizures or sudden death. An apnea monitor is recommended; intervention for feeding difficulties is required; 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 treat a progressive thoracolumbar scoliosis. Sweating triggered by cold or apprehension can be effectively treated with clonidine alone or combined with amitriptyline. Moxonidine may also be tried.

Surveillance: Monitor for scoliosis.

Agents/circumstances to avoid: Heat exposure and prolonged physical activity in a 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. The prescription of clonidine should not be discontinued abruptly; the drug should be phased out over four to six days.

Genetic counseling.

Cold-induced sweating syndrome (CISS) and its infantile version, 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. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if both pathogenic variants in the family are known.

Diagnosis

Suggestive Findings

Cold-induced sweating syndrome (CISS) or its infantile presentation (Crisponi syndrome) should be suspected in individuals with the following cardinal clinical characteristics:

  • Dysmorphic features present at birth (Figure 1A, Figure 1B) including:
    • Round face
    • Low-set ears
    • Depressed nasal bridge and anteverted nares
    • Long philtrum, high-arched palate, and micrognathia
    • 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 (limited to the lumbar region, groin, and thighs) in heat, may result in uncomfortable overheating
    • Temperature spiking (≤42º C [108º F]) in infancy not associated with infections, leading in some individuals to seizures and sudden death
  • Progressive thoracolumbar kyphoscoliosis requiring bracing or surgical intervention in the second decade
Figure 1. 

. A.

Figure 1.

A. Newborn with Crisponi syndrome, caused bybiallelic CRFL1 pathogenic variants, showing camptodactyly with fisted hands and characteristic facial features (rounded face, poorly developed and depressed nasal bridge, anteverted nares, long philtrum, facial (more...)

Figure 2.

. A.

Figure 2.

A. 18-month-old girl with Crisponi syndrome, caused by biallelic CLCF1 pathogenic variants, demonstrating typical facial muscle contraction and puckering of the lips. Note the characteristic erythematous rash over the cheeks.

B. Younger (more...)

Figure 3. . Infant with Crisponi syndrome, caused by CLCF1 biallelic pathogenic variants, demonstrating the tendencies to grimace and startle while being handled.

Figure 3.

Infant with Crisponi syndrome, caused by CLCF1 biallelic pathogenic variants, demonstrating the tendencies to grimace and startle while being handled. The infant assumes an extensor posture, retracting the head and raising and flexing the arms.

Establishing the Diagnosis

The diagnosis of CISS is established in a proband with the above clinical features. Identification of biallelic pathogenic variants in CRLF1 or CLCF1 on molecular genetic testing (see Table 1) establishes the diagnosis if clinical features are inconclusive.

Molecular testing approaches can include serial single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

Serial single-gene testing

1.

Sequence analysis of CRLF1

2.

Sequence analysis of CLCF1 if no pathogenic variants in CRLF1 are identified.

3.

Deletion/duplication analysis of CRLF1

Note: Sequence analysis of LIFR is recommended if no pathogenic variants in CRLF1 and CLCF1 are identified (see Differential Diagnosis).

A multi-gene panel that includes CRLF1, CLCF1 and other genes of interest (see Differential Diagnosis) may also be considered. (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost.

More comprehensive genomic testing (when available) including whole-exome sequencing (WES) and whole-genome sequencing (WGS) may be considered if serial single-gene testing (and/or use of a multi-gene panel) fails to confirm a diagnosis in an individual with features of CISS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation). For issues to consider in interpretation of genomic test results, click here.

Table 1.

Molecular Genetic Testing Used in Cold-Induced Sweating Syndrome Including Crisponi Syndrome (CISS)

Gene 1Proportion of CISS Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detected by Test Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
CRLF1~95%~99% 54 individuals 6
CLCF1~5%~100% 7Unknown 8
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

37 distinct CRLF1 pathogenic variants were identified in 59 individuals from 49 families [Piras et al 2014].

6.

Four large deletions involving parts of CRLF1 have been reported [Di Leo et al 2010, Piras et al 2014].

7.

Four distinct CLCF1 pathogenic variants were found in three individuals from two families [Hahn et al 2010].

8.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

Cold-induced sweating syndrome (CISS) can present to the clinician in infancy as Crisponi syndrome, or from age three years onward as cold-induced sweating [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 individuals had findings of Crisponi syndrome in infancy, some more severe than others [Hahn et al 2010].

Presentation in Infancy (Crisponi Syndrome)

Typical dysmorphic features (see Suggestive Findings) 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. At the same time, they may also develop laryngospasm, difficulty breathing, and circumoral cyanosis as a sign of anoxia.

Life-threatening respiratory difficulties and unexplained high fevers up to 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.

Affected infants usually begin to feed normally by age one to two years. Occasionally, dysphagia persists throughout the first decade and may be associated with lack of interest in food or liquids. Excessive startling disappears by age two years. Psychomotor and speech development can be delayed due to manual difficulties caused by camptodactyly and orofacial weakness, respectively [Hahn et al 2010].

Presentation in Childhood and Adulthood

Cold-induced sweating, the most disabling symptom in adulthood, is recognized during the first decade (from age 3 years). With environmental temperatures of ≤22°C (72º F), affected individuals sweat profusely on their face and upper body, accompanied by intense shivering and dermal vasoconstriction, so that the fingers appear cold and cyanotic. 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.

Toward 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 been observed in rare cases, 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; preliminary data established with use of the laser-evoked potential technique suggest that functions of facial and hand cutaneous nociceptive and warmth pathways are normal in CRLF1-associated CISS [Testani et al 2015]. This deserves further study.

Developmentally abnormal autonomic innervation of sweat glands and skin adnexa was documented with immunohistochemical techniques in skin biopsies derived from individuals with CRLF1-associated CISS and Stüve-Wiedemann syndrome (STWS), who exhibited cold-induced sweating. Findings demonstrate persistence of noradrenergic innervation of sweat glands in the hyperhidrotic skin, indicating that sympathetic neurons innervating sweat glands failed to undergo postnatal cholinergic differentiation [Di Leo et al 2010, Melone et al 2014].

The following additional tests could be performed to explore further the possibility of impaired development of sensory and autonomic neurons:

  • Study of nociceptive cutaneous Aδ and warmth C-fibers using CO2 laser-evoked potentials with recording from perioral, hand, and when possible lower leg
  • Quantitative sensory testing (QSART)
  • Nerve biopsies with morphometric analyses and ultrastructural evaluation
  • Skin biopsy with quantitative analysis of sensory innervation
  • Skin biopsy with immunohistochemical studies for the evaluation of autonomic innervation of sweat glands, arteriovenous anastomoses, and piloerector muscles

Genotype-Phenotype Correlations

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

CRLF1 pathogenic variants are distributed throughout the entire gene. A large study by Piras et al [2014] found no correlation between phenotype and the type/localization of CRLF1 pathogenic variants.

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 pathogenic variants 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

CRLF1-associated CISS has been observed in individuals originating from Europe, Turkey, the Middle East, India, Pakistan, East Asia, Australia, and North and Central 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, Di Leo et al 2010, Hahn et al 2010, Yamazaki et al 2010, Cosar et al 2011, Herholz et al 2011, Dessì et al 2012, Hakan et al 2012, Tüysüz et al 2013, Piras et al 2014]. CRLF1-associated CISS appears to be particularly prevalent in the Mediterranean region [Crisponi 1996, Crisponi et al 2007, Dagoneau et al 2007].

The majority of CRLF1 pathogenic variants are private. A few pathogenic variants were prevalent in unrelated individuals from certain geographic regions and likely derive from a founder effect (e.g., c.226T>G and c.676_677dupA in Sardania, c.708_709delinsT in Turkey, and c.713dupC in Spain, Turkey, the Roma population, and Central America) [Piras 2014, personal observation].

To date only three individuals with CLCF1-associated CISS have been reported [Hahn et al 2006, Hahn et al 2010].

Differential Diagnosis

Stüve-Wiedemann syndrome (STWS) (OMIM). In the infantile period, STWS 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. A few of the 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] and personally observed [Hahn, unpublished]. In their teens survivors may manifest dental decay and progressive kyphoscoliosis [Jung et al 2010]. STWS is associated with LIFR pathogenic variants and is inherited in an autosomal recessive manner.

Melone et al [2014] reported a 33-year-old female with features of STWS including cold-induced sweating, but without bowing of the long bones and complete chromosome 5 maternal isodisomy with an isozygous LIFR pathogenic variant (c.2170C>G, p.Pro724Ala). The proband’s mother was heterozygous for the c.2170C>G variant.

Jung et al [2010] reported several individuals with a typical STWS phenotype who did not have pathogenic variants in LIFR. 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 DA2A (Freeman-Sheldon syndrome; OMIM), caused by pathogenic variants in MYH3 and to distal arthrogryposis type DA2B (Sheldon-Hall syndrome; OMIM), also caused by pathogenic variants in MYH3 in some individuals. 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. Distal arthrogryposis type 2A and type 2B are inherited in an autosomal dominant manner.

Chong et al [2015] reported that in a subset of individuals with DA2A without pathogenic variants in MYH3, heterozygous pathogenic missense variants in NALCN (predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments) were associated with congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD syndrome; OMIM). Biallelic pathogenic variants in other regions of NALCN are associated with an autosomal recessive syndrome of severe infantile feeding difficulties, speech delay, hypotonia, and severe cognitive impairment (OMIM) [Al-Sayed et al 2013, Fukai et al 2016]; the latter two features are not seen in CISS.

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, Tüysüz et al 2013]
  • Swallowing tests and esophageal manometry. May be helpful in assessing the safety of oral feeding
  • EEG when seizures are observed or suspected
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Infants require close monitoring in anticipation of episodes of laryngospasm with respiratory distress, bouts of hyperthermia (≤42º C [108° F]), 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.
  • Nasogastric or gastrostomy tube feeding is indicated until at least age one year to overcome precarious feeding problems in infancy.
  • 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 adults 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, 10 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]. Moxonidine was well tolerated in the short term; 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 with CISS may conceive normally. No complications during pregnancy have been reported to date.

Treatments for cold-induced sweating (clonidine, amitriptyline, moxonidine) 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 child are obligate heterozygotes (i.e., carriers of one CRLF1 or CLCF1 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with CISS are obligate heterozygotes (carriers) for a pathogenic variant in CRLF1 or CLCF1.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a CRLF1 or CLCF1 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the CRLF1 or CLCF1 pathogenic variants in the family.

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 and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the CRLF1 or CLCF1 pathogenic variants have been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for CISS are possible options.

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

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.

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 from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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 belong to the IL6 family of cytokines, which share a common signal transducer gp130/LIFR and play a role in the embryonic development and differentiation of motor, sensory, and autonomic neurons. They also play a role in bone formation during development and in the ongoing remodeling of endochondral bone [Sims 2015]. CRLF1 and CLCF1 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 abnormal sweating is observed in both CISS and Stüve-Wiedemann syndrome (STWS) (caused by pathogenic variants in LIFR), which indicates that both components of the gp130/LIFR signal transducers are required for the cholinergic differentiation of sympathetic neurons that innervate mature sweat glands [Stanke et al 2006].

Thus all components in the CNTFRα/gp130/LIFRβ tripartide complex play an essential role in the postnatal switch from the embryonic noradrenergic to the mature cholinergic phenotype of the sympathetic neurons innervating sweat glands. It was recently shown in individuals with CRLF1-associated CISS and STWS that in areas of skin with manifest cold-induced sweating the innervation of sweat glands remained noradrenergic (i.e., the switch to a cholinergic transmitter phenotype had not occurred). Moreover, the unusually reduced sweating in the lower limbs was caused by developmental derangement of sensory innervation and atrophy of sweat glands [Di Leo et al 2010, Melone et al 2014].

CRLF1

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

Benign allelic variants. The first 37 amino acid residues of CRLF1 represent a signal peptide. This sequence contains five adjacent leucines. 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].

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

Two homozygous variants, c.242G>A and c.1121T>G, were observed in two Israeli sisters from a consanguineous family. The disease-causing variant in this family has not been determined, although, according to prediction software, the variant c.1121T>G is likely pathogenic [Sohar et al 1978, Knappskog et al 2003, Piras et al 2014].

Table 2.

Selected CRLF1 Allelic Variants

Variant ClassificationDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Benignc.75_77delGCTp.Leu26delNM_004750​.4
NP_004741​.1
c.242G>Ap.Arg81His
Pathogenicc.31_53del23p.Gln11ValfsTer68
c.303delCp.Asn102ThrfsTer47
c.397+1G>Ap.?
c.413C>Tp.Pro138Leu
c.538C>Tp.Gln180Ter
c.845_846delTGp.Val282GlyfsTer47
c.852G>Tp.Trp284Cys
c.935G>Ap.Arg312His
c.1121T>Gp.Leu374Arg
Exon 6-9 deleted 1p.?

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.

Described by Di Leo et al [2010]

Normal gene product. CRLF1/CLCF1 heterodimers are required for CNTFR/gp130/LIFR activation and STAT3 signaling [Rousseau et al 2006, Hahn et al 2010].

Periosteum, the connective tissue surrounding bone, 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].

Although the molecular identity of the cholinergic differentiation factor remains to be defined, CRLF1/CLCF1 are possible candidates as regulators of this postnatal neurotransmitter switch by signaling through CNTFRα/gp130/LIFRβ [Habecker et al 1995, Habecker et al 1997, Asmus et al 2001]. The known expression of CRLF1/CLCF1 on the surface of developing sweat glands lends support for this hypothesis [Stanke et al 2006].

Abnormal gene product. The functional consequences of observed CRLF1 pathogenic variants are primarily loss of function. 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 [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].

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.

Pathogenic allelic variants. Only four putative causative variants in two families are published. Multiexon 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 pathogenic no-stop variant 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. CRLF1/CLCF1 heterodimers are required for cytokine secretion. CLCF1-binding to CNTFRα results in the recruitment and dimerization of gp130 and LIFRβ with subsequent phosphorylation and activation of STAT3 [Sims 2015].

Abnormal gene product. See CRLF1, Abnormal gene product.

References

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Chapter Notes

Revision History

  • 17 March 2016 (sw) Comprehensive update posted live
  • 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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