Clinical characteristics.

Cold-induced sweating syndrome (CISS) and its infantile presentation, Crisponi syndrome(CS) is characterized by dysmorphic features (distinctive facies, lower facial weakness, flexion deformity at the elbows, camptodactyly with fisted hands, misshapen feet, and overriding toes); intermittent contracture of facial and oropharyngeal muscles when crying or being handled with puckering of lips and drooling of foamy saliva often associated with laryngospasm and respiratory distress; excessive startling and opisthotonus-like posturing with unexpected tactile or auditory stimuli; poor suck reflex and severely impaired swallowing; and a scaly erythematous rash. During the first decade of life, children with CISS/CS develop profuse sweating of the face, arms, and chest with ambient temperatures below 18º to 22º C, and with other stimuli including nervousness or ingestion of sweets. Affected individuals sweat very little in hot environments and may feel overheated. Progressive thoracolumbar kyphoscoliosis occurs, requiring intervention in the second decade.

Diagnosis/testing.

The diagnosis of CISS/CS is established in a proband with suggestive findings and biallelic pathogenic variants in either CLCF1 or CRLF1 identified on molecular genetic testing

Management.

Treatment of manifestations: Supplemental oxygen is needed for laryngospasm with respiratory distress and cooling blankets for bouts of hyperthermia; intervention for feeding difficulties is necessary over the first year of life; bracing and physical therapy for camptodactyly and prolonged bracing or surgical intervention may be required to treat a progressive thoracolumbar scoliosis. Topical lubrication needed to avoid corneal alterations and regular dental care needed to avoid excessive dental decay. Options for the treatment of cold-induced sweating include clonidine alone, clonidine plus amitryptyline, or moxonidine alone.

Surveillance: Evaluate for scoliosis. Ophthalmologic evaluation for corneal injury every six months and yearly dental visits due to early dental decay are recommended.

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.

CISS/CS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CLCF1 or CRLF1 pathogenic variant, each sib of an affected individual has at conception 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 the CLCF1 or CRLF1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

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

• Dysmorphic features present at birth (Figure 1A, Figure 1B) including:
  • Round face
  • Chubby cheeks
  • 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 facial and oropharyngeal muscles when crying or being handled, with puckering of the lips and drooling of foamy saliva
  • Normal facial expression when relaxed or sleeping (Figure 1B)
  • Typically, excessive startling and opisthotonus-like posturing with unexpected tactile stimuli or loud noises (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
  • Affecting the face, fingers, and occasionally trunk
• Paradoxic, 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) or on exposure to a cold draft or cold drink
  • Sweating is also observed with nervousness and ingestion of sweets (illustrated in Hahn et al [2006]).
• Other thermoregulatory abnormalities
  • Minimal sweating in heat (limited to the lumbar region, groin, and thighs) that may result in uncomfortable overheating
  • In infancy, recurrent temperature spikes up to 42º C (108º F), not associated with infections, leading, in some children, to seizures and at times, to sudden death
• Progressive thoracolumbar kyphoscoliosis requiring bracing or surgical intervention in the second decade

Figure 1

A. Newborn with Crisponi syndrome, caused by biallelic 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. Girl age 18 months 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 sister to A at (more...)

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/CS is established in a proband with suggestive findings and biallelic pathogenic variants in either CLCF1 or CRLF1 on molecular genetic testing (see Table 1).

Note: Identification of biallelic CLCF1 or CRLF1 variants of uncertain significance (or identification of one known CLCF1 or CRLF1 pathogenic variant and one CLCF1 or CRLF1 variant of uncertain significance) does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of CISS/CS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

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 syndrome. Interviews with mothers of children or adults with CISS, review of a targeted questionnaire completed by caregivers of the infants, and review of early medical records revealed that probably all individuals had findings of CS in infancy, some more severe than others [Hahn et al 2010].

To date, 99 individuals have been identified with biallelic pathogenic variants in either CLCF or CRLF1 [Hahn et al 2010; Buers et al 2020a; Buers et al 2020b; Schierz et al 2020; Authors, personal observations]. The following description of the phenotypic features associated with this condition is based on these reports.

Genotype-Phenotype Correlations

Clinical manifestations are identical in individuals with CLCF1 or CRLF1 pathogenic variants [Hahn et al 2010].

No genotype-phenotype correlations for either CLCF1 or CRLF1 have been identified [Piras et al 2014].

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.

With time, survivors of infantile-onset Crisponi syndrome [Crisponi 1996] will develop CISS, substantiated by the identification of pathogenic variants in CRLF1 [Buers et al 2020a] or CLCF1 [Hahn et al 2006, Hahn et al 2010]. Thus, CISS and Crisponi syndrome are not "allelic disorders," but rather Crisponi syndrome is the infantile presentation of CISS [Dagoneau et al 2007, Hahn et al 2010].

Prevalence

CISS/CS has been observed in individuals originating from every continent except Africa. CRLF1-associated CISS/CS appears to be particularly prevalent in the Mediterranean region [Piras et al 2014, Buers et al 2020a].

To date only four individuals with CLCF1-associated CISS/CS have been reported [Hahn et al 2010, Buers et al 2020b].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CISS/CS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Note: Any evaluation of an infant needs to proceed with extreme care in handling to avoid startling the infant, which can result in laryngospasm. Supplemental oxygen and a cooling blanket need to be readily available at the bedside.

Treatment of Manifestations

Management by multidisciplinary specialists including neonatologist, pediatrician, neurologist, geneticist, gastroenterologist, dermatologist, orthopedist, hand surgeon, dietician, physical therapist, occupational therapist, speech therapist, psychologist, dentist is recommended.

Infants with CISS/CS are extremely fragile and require special care, including the following:

• Continuous monitoring of cardiorespiratory parameters with supplementary oxygen readily available
• Room temperature or incubator temperature constant at 20° C
• Quiet and somewhat darkened room
• Gentle handling for diaper changes and turning
• Minimized painful stimuli such as venipunctures
• Preparedness for hyperthermic crisis (cooling blankets on site)
• Preparedness for seizures (associated with hyperthermia) and respiratory distress

Other specific treatments are listed in Table 5.

Prevention of Primary Manifestations

See Treatment of Manifestations.

Surveillance

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/CS 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. Clonidine should not be discontinued abruptly, but rather phased out over four to six days.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

Cold-induced sweating syndrome / Crisponi syndrome (CISS/CS) is 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., presumed to be carriers of one CRLF1 or CLCF1 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CRLF1 or CLCF1 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a CRLF1 or CLCF1 pathogenic variant, each sib of an affected individual has at conception 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/CS 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 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 and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

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

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The ciliary neurotrophic factor receptor (CNTFR) pathway supports the differentiation and survival of a wide range of neuronal cell types (motor, sensory, and autonomic) during development and in adult life. CLCF1 and CRLF1 (encoded by CLCF1 and CRLF1 respectively) are secreted as a stable heterodimeric complex CRLF1/CLCF1 and act as a functional ligand to CNTFR. Pathogenic variants in CLCF1 or CRLF1 cause cold-induced sweating syndrome / Crisponi syndrome (CISS/CS) through failure of activation of the CNTFR pathway.

Mature sweat glands are known to be innervated by cholinergic sympathetic neurons. However, at birth immature sweat glands retain their embryonic noradrenergic sympathetic innervation. As sweat glands mature postnatally, they secrete a retrogradely acting cytokine which directs the innervating sympathetic neurons to change their transmitter phenotype from noradrenergic to cholinergic [Schotzinger et al 1994]. Members of the IL6 family of cytokines, in particular CLCF1 and CRLF1, were considered likely candidates to be involved in CISS/CS [Habecker et al 1997, Stanke et al 2006].

Skin biopsies from an individual with CISS associated with pathogenic variants in CRLF1 demonstrated failure of cholinergic differentiation of sympathetic neurons innervating sweat glands [Di Leo et al 2010]. Skin biopsies from areas of cold-induced hyperhidrosis at the shoulder showed relatively preserved epidermal and dermal sensory innervation, yet sweat glands lacked the normally rich cholinergic innervation and retained instead an ample supply of noradrenergic sympathetic fibers. These observations suggested a failed switch of adrenergic to cholinergic sympathetic innervation of sweat glands, as the cause of paradoxic sweating.

Biopsies from the glabrous skin and from anhidrotic hairy skin (fingertip and leg, respectively) revealed length-dependent severe dermal sensory and autonomic denervation involving sweat glands and all skin adnexa, and the complete absence of cholinergic nerves, with few residual sweat glands and noradrenergic fibers present. These findings indicate a severe, possibly developmental derangement of cutaneous somatic and autonomic innervation, providing an explanation for the unusual reduction of sweating in the lower limbs and possibly also for the impaired pain perception reported in a proportion of individuals with CISS/CS [Knappskog et al 2003].

Infants with CISS/CS manifest lower facial weakness and inability to suckle and swallow. Mouse pups with targeted deletions of Crlf1, Clcf1, Cntfr, or Lifr display an identical phenotype and demonstrate inability to suckle. They die shortly after birth from malnutrition and are found to have a reduced number of facial and lumbar motor neurons [Forger et al 2003]. These observations exemplify that each component of the CNTFR signaling pathway plays an important role in early development and survival.

Mechanism of disease causation. The functional consequences of observed CLCF1 and 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 the CNTFRα/gp130/LIFR pathway and thereby to failure of downstream STAT3 signaling [Heinrich et al 2003, Rousseau et al 2006].

Gene-specific laboratory considerations: CRLF1

• Due to its high GC content of exon 1, CRLF1 may be difficult to amplify and sequence. Adding of betaine or ³GC-enhancer² is recommended.
• The frequent p.Leu26del variant (allele frequency of 0.2 in gnomAD Database) may also cause problems in interpreting the exon 1 sequence; sequencing of both strands is recommended.

Author Notes

Dr Angelika F Hahn can be contacted directly at [email protected].

Dr Per Morten Knappskog can be contacted directly at [email protected].

Acknowledgments

The authors wish to recognize the invaluable contributions to this work from the late Prof Dr Helge Boman, MD, PhD, Prof Stefan Johansson, PhD, and Prof Maria Nolano, MD.

Author History

Helge Boman, MD, PhD; Haukeland University Hospital, Bergen (2011-2021)
Angelika F Hahn, MD, FRCP (2011-present)
Per Morten Knappskog, PhD (2021-present)

Revision History

• 12 August 2021 (ha) Comprehensive update posted live
• 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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