Cold-Induced Sweating Syndrome Including Crisponi Syndrome

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2021-01-18

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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
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)
- 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. 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...)

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 multigene 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 multigene 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 are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene 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 an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

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

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

1.: See Table A. Genes and Databases for chromosome locus and protein.
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 used may 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 2016]. 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 601559). 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 paradoxic 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 193700), caused by pathogenic variants in MYH3 and to distal arthrogryposis type DA2B (Sheldon-Hall syndrome; OMIM 601680), 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 616266). 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 615419) [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.

Paradoxic 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 sibs 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 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.