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 nostrils, 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 3A) 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 2)

• 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 3B)

• Scaly erythematous rash (Figure 3A)

  • 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, leading in some cases to seizures and sudden death

• Progressive thoracolumbar kyphoscoliosis requiring bracing or surgical intervention in the second decade

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 nostrils, long philtrum, facial grimacing, and tightly (more...)

Figure

Figure 3. 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 A (CISS2) at a similar age; note the (more...)

Figure

Figure 2. 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, also known as CLF, CLF-1), a class I cytokine receptor, represents the major locus for CISS (CISS1) [Knappskog et al 2003].

• CLCF1 (cardiotrophin-like cytokine factor 1, also known as CLC, BSF-3), 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.

Research testing

• Sequence analysis. Mutations in CRLF1 or CLCF1 are found in most (~95%) families evaluated by conventional sequence analysis of the coding region and associated intron boundaries.

  • CRLF1 mutations include missense, nonsense, splicing, and frameshift mutations resulting from small intragenic insertions, deletions and indels. Sequence analysis typically does not detect deletion of exon(s) or the entire gene (see Table 2).

  • CLCF1 mutations include missense, nonsense, and elongation stop codon mutations (see Table 3).

• Deletion/duplication analysis

  • CRLF1. One large deletion involving parts of CRLF1 has been reported [Di Leo et al 2010] (see Molecular Genetics). Deletion analysis can be performed by a variety of methods (Table 1, footnote 4) and is an efficient second-tier testing strategy after sequence analysis.

  • CLCF1. Deletions involving CLCF1 have not been described.

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 a typically affected individual strongly indicates compound heterozygosity for a second unidentified mutation and warrants deletion analysis. See Table 1, footnote 4 for methods.

  • Clinical confirmation of mutations identified in a research laboratory may be available. See .

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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in CRLF1 or CLCF1.

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 (see Hahn et al [2010]).

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 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.

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 Near East, India, the Far East 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]. 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].

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:

• MRI of brain is usually normal but may be done to evaluate for complicating features such as 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 done to assess the safety of oral feeding.

• EEG should be performed when seizures are observed or suspected.

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, such as 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. Seizure medication 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 triggered by cold or apprehension can be effectively treated with an individualized prescription of clonidine either alone or combined with amitriptyline (rationale and approach to therapy are detailed in Hahn et al [2006], Hahn et al [2010]) or of monoxidine [Herholz et al 2010].

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.

Testing of Relatives at Risk

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

Therapies Under Investigation

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

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

Risk to Family Members

This section is written from the perspective that molecular genetic testing for this disorder is available on a research basis only and results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis.— ED.

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

Carrier testing of at-risk relatives may be available from laboratories offering clinical confirmation of mutations identified in research laboratories if the disease-causing mutations in the family have been identified. See .

Related Genetic Counseling Issues

See Management, Testing Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk 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 or 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

No laboratories listed in the GeneTests Laboratory Directory offer molecular genetic testing for prenatal diagnosis of CISS. However, prenatal testing may be available for families in which the disease-causing mutations have been identified. For laboratories offering custom prenatal testing, see .

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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 CRLF1/CLCF1 to CNTFR results in the recruitment, binding and dimerization of glycoprotein 130 (gp130) and of 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 CNTFR exhibited profound motor neuron deficits and died shortly after birth, while mice and humans deficient of CNTF, the primary ligand to CNTFR, were healthy [Takahashi et al 1994, DeChiara et al 1995]. Moreover, targeted deletions of the murine orthologs of the human CLCF1, CRLF1, 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 complete uninterest in food and drink. The observations illustrate the importance of the CNTFR/gp130/LIFR tripartite receptor and its ligand CLCF1/CRLF1 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 with 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] (see Hyperekplexia). 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.

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 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 [Habecker et al 1997]. From these cytokines LIF, CTNF, and CT-I were ruled out, leaving CRLF1/CLCF1 as possible candidates [Habecker et al 1995, Asmus et al 2001].

In one individual with CISS2 the authors have shown that the identified mutations in CLCF1 abrogate CLCF1 binding to CNTFR, resulting in lack of activation of gp130/LIFR and failure of STAT3 signaling [Rousseau et al 2006]. Mutations in CLCF1 that have been identified in CISS2 are predicted to result in nonfunctional CLCF1 [Hahn et al 2010, Table 3]. The functional consequences of observed mutations in CRLF1 in CISS1 have not yet been studied, but most identified CRLF1 sequence variants are predicted to 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, Table 2]. Thus, it would seem plausible that loss of function in one component of CRLF1/CLCF1 complex leads to lack of activation of gp130/LIFR and failure of downstream STAT3 signaling.

Target-dependent cholinergic differentiation of sympathetic neurons that innervate mature sweat glands is dependent on gp130 signaling [Stanke et al 2006]. Skin biopsies of an individual with CISS1 that were derived from areas of hyperhidrosis illustrate that the sweat glands lacked cholinergic innervation while adrenergic supply was amply maintained [Di Leo et al 2010]. These observations require further study. If upheld, the findings would indirectly support a role for CLCF1/CRLF1 in mediating the switch from noradrenergic to cholinergic properties of sympathetic neurons that innervate mature sweat glands and possibly also those that innervate periosteum.

Literature Cited

1. Asmus SE, Parsons S, Landis SC. Developmental changes in the transmitter properties of sympathetic neurons that innervate periosteum. J Neurosci. 2000;20:1495–1504. [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. 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]
5. 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]
6. 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]
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. 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: PMC2821174] [PubMed: 20162032]
9. 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]
10. 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]
11. 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]
12. 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]
13. Francis NJ, Landis SC. Cellular and molecular determinants of sympathetic neuron development. Annu Rev Neurosci. 1999;22:541–66. [PubMed: 10202548]
14. 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]
15. Habecker BA, Pennica D, Landis SC. Cardiotrophin-1 is not the sweat gland-derived differentiation factor. Neuroreport. 1995;7:41–4. [PubMed: 8742412]
16. 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]
17. 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]
18. 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]
19. 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]
20. 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]
21. Heymann D, Rousselle A-V. gp130 cytokine family and bone cells. Review article. Cytokine. 2000;12:1455–68. [PubMed: 11023660]
22. 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]
23. 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]
24. Li M, Sendtner M, Smith A. Essential function of LIF receptor in motor neurons. Nature. 1995;378:724–7. [PubMed: 7501019]
25. 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]
26. 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. PNAS. 2006;103:10068–73. [PMC free article: PMC1502507] [PubMed: 16782820]
27. 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]
28. Sims NA, Walsh NC. GP130 cytokines and bone remodelling in health and disease. BMB Rep. 2010;43:513–23. [PubMed: 20797312]
29. 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]
30. 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. [PubMed: 19191755]
31. 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]
32. 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]
33. 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: 18074358]
34. 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, p 733. Honolulu, Hawaii: American Society of Human Genetics 59th Annual Meeting; 2009. Available at www.ashg.org.
35. 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]
36. Yang Y. Skeletal morphogenesis during embryonic development. Crit Rev Eukaryot Gene Expr. 2009;19:197–218. [PubMed: 19883365]
37. 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]

Revision History

• 3 March 2011 (me) Review posted live

• 1 June 2010 (hb) Original submission