Cold-induced sweating syndrome A report of two cases and demonstration of genetic heterogeneity

Journal of the Neurological Sciences 250 (2006) 62 – 70 www.elsevier.com/locate/jns

Cold-induced sweating syndrome A report of two cases and demonstration of genetic heterogeneity A.F. Hahn a,⁎, D.L. Jones b , P.M. Knappskog c,d , H. Boman c,d , J.G. McLeod e a

b

Department of Clinical Neurological Sciences, London Health Science Center, University of Western Ontario, London, Canada N6A 5A5 Departments of Physiology and Pharmacology and Medicine, Lawson Health Research Institute, University of Western Ontario, London, Canada c Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway d Section of Medical Genetics and Molecular Medicine, Department of Clinical Medicine, University of Bergen, Bergen, Norway e Institute of Clinical Neuroscience, Royal Prince Alfred Hospital and University of Sydney, Sydney, NSW 2006, Australia Received 7 June 2006; accepted 12 July 2006 Available online 6 September 2006

Abstract Objectives: To characterize the specific autonomic disturbances underlying the cold-induced sweating syndrome (CISS), and to describe a novel genetic variant of this rare recessive disorder. The two not previously reported patients had similar dysmorphic features: abnormal facial appearance, high arched palate, low set rotated ears, flexion deformities of elbows and fingers and scoliosis. Most noticeable were their paradoxical sweat responses: cold ambient temperature induced a profuse sweating over the face, arms and trunk but not over the lower limbs; while in the heat very little sweating occurred primarily on the legs. Testing of autonomic functions demonstrated normal cardiovascular reflexes and postganglionic sympathetic efferent functions. Sural nerve morphology and number of unmyelinated fibers was normal and skin biopsies showed normal appearing eccrine sweat glands. MRI scans revealed no structural brain abnormalities. Oral clonidine, prescribed in one patient, completely suppressed cold-induced sweating. Observed clinical features matched those of two sisters reported from Israel and of two brothers reported from Norway. All six cases presented a similar phenotype. The Norwegian, Israeli and Canadian cases were homozygous or compound heterozygous, respectively, for mutations in the CRLF1 gene on chromosome 19p12 (CISS1). The Australian case, however, had no pathogenic sequence variants in the CRLF1 gene, but was compound heterozygous for mutations in the CLCF1 gene on chromosome 11q13.3 (CISS2). Conclusion: The rare cold-induced sweating syndrome is genetically heterogeneous and is probably caused by central and peripheral impairment of sudomotor functions. This is the first detailed report on the clinical consequences of mutations in the CLCF1 gene in humans. Directions for medical therapies are outlined to achieve long term symptom control. © 2006 Elsevier B.V. All rights reserved. Keywords: Cold-induced sweating; CISS; CISS2; CRLF1; CLF; CLCF1; CLC

1. Introduction In 1978, Sohar et al. [1] described a new entity of ‘coldinduced sweating’ in two Israeli sisters who experienced excessive sweating and piloerection over the upper part of the back, chest and upper limbs when external temperatures were lowered below 18 °C. Both also had dysmorphic features of high arched palate, nasal voice, under developed ⁎ Corresponding author. Tel.: +1 519 663 3110; fax: +1 519 663 3328. E-mail address: [email protected] (A.F. Hahn). 0022-510X/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2006.07.001

nasal bridge, inability to fully extend the elbows, hammer toes and slight kyphoscoliosis. A peripheral mechanism for the abnormal sweating was postulated. Subsequently, a patient was reported, who had experienced episodes of sweating induced by cold, where MR imaging of the brain revealed a basal forebrain malformation [2]. The authors concluded that the primary pathophysiology was hypothalamic dysregulation. More recently, Knappskog et al. [3] performed genetic studies, and the Israeli sisters as well as two Norwegian brothers with similar clinical manifestations were found to be homozygous for mutations in the CRLF1

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gene on chromosome 19p12, confirming an autosomal recessive mode of inheritance. Here we report a Canadian and an Australian patient with cold-induced sweating and physical abnormalities similar to those described previously [1,3]. Autonomic function studies were performed in both patients, in an attempt to define the site of the abnormality in the sudomotor control mechanism. Genetic studies were undertaken and the likely causative mutations identified in both cases. The data was reported at the XVIII World Congress of Neurology Meeting, Sydney, Australia, 2005 [4]. A brief summary of Case 2 is also given in Ref. [9] that reports on the functional consequences of the identified mutations in the CLCF1 gene. 2. Materials and methods 2.1. Tests of autonomic function The tests were undertaken using conventional methods [5,6]. 2.2. Sural nerve biopsy The biopsy and morphometry of myelinated and unmyelinated fibers were performed using standard techniques [7]. 2.3. Genetic studies DNA sequencing and mutation detection was performed as previously described [3]. The gene nomenclature follows the recommendations of HUGO Gene Nomenclature Committee (http://www.gene.ucl.ac.uk/nomenclature/). Alternative names for cardiotrophin-like cytokine factor 1 (CLCF1) have been CLC, BSF-3, NNT1, and NR6, and for cytokine receptor-like factor 1 (CRLF1) CLF and CLF-1. The cDNA sequences of CRLF1 and CLCF1 are found in the NCBI database (http://www3.ncbi.nlm.nih.gov/) as NM_004750.2 and NM_013246.2, respectively. The mutation nomenclature used is as recommended by The Human Genome Variation Society (http://www.genomic.unimelb.edu.au/mdi/rec.html). 3. Case reports 3.1. Case 1 A woman aged 24 years had been troubled all her life by excessive sweating, triggered by exposure to cold, eating sweets and by apprehension and fear. Instantaneously she would break out in profuse sweating of the face, the anterior and posterior chest down to the waist, the axillae and arms, with exception of the palms. In winter, perspiration would soak her garments thus perpetuating the chills, and her nose and fingers would blanch and become cold and stiff. Paradoxically, she was not aware of any sweating in the heat but had observed

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piloerection on her thighs. The hyperhidrosis, a source of considerable embarrassment and discomfort, was partially corrected by transdermal scopolamine. Habituation and increasing side effects forced her to discontinue the medication after 6 years and to seek additional medical help. There were no other symptoms of autonomic dysfunction or peripheral neuropathy. In infancy she had shown difficulty feeding and required brief hospitalization. The examination revealed dysmorphic features of a narrow face and high arched palate with nasal speech, low set posteriorly rotated ears, short stature, mild thoracolumbar scoliosis, cubitus valgus and flexion contractures of the elbows and the third and fourth fingers (camptodactyly) and syndactyly of the second and third toes. The neurological examination was normal. Her parents were unrelated and they and nine siblings were unaffected. The patient is now married with two healthy children. Laboratory studies were normal including full blood count, liver function tests, serum electrolytes, serum and urine osmolarity, sweat electrolytes and osmolarity, thyroid function tests, plasma luteinizing and follicular stimulating hormones, plasma testosterone, resting plasma adrenaline, noradrenaline, dopamine, renin and vasopressin. Chest X-ray, ECG, MRI of the brain and the adrenal glands were normal. Motor and sensory nerve conduction studies (median, ulnar, peroneal, tibial and sural nerves) and needle EMG (first dorsal interosseous and tibialis anterior muscles) were normal at age 24 and when repeated at 42 years. A fascicular biopsy of the sural nerve at the ankle was normal on light and electron microscope examination and showed a regular complement (36,300 fibers/mm2) and frequency distribution of unmyelinated fibers. A punch biopsy of the skin from the posterior chest showed a normal density and histological appearance of eccrine sweat glands. 3.2. Sweat tests During testing of thermoregulatory and cold-induced sweating, thermistor probes were applied to the tympanic membrane to record core temperature, and to the mid-anterior and posterior chest, the index finger and the thigh. Room temperature (RT) and room humidity (RH) were monitored. Samples were drawn for plasma noradrenaline, adrenaline, dopamine and vasopressin while supine and while sitting at RT 27 °C, and after exposure to RT 25, 22 and 19 °C during coldinduced sweating. Measurements were performed at baseline and after treatment with clonidine for 4 days and for 6 weeks. 3.3. Sweating produced by excitement In apprehension of the first experiment, during the application of quinizarin powder and the thermistor probes, there was profuse sweating on the eyebrows, nose, cheeks and upper lip, the anterior and posterior chest just above the umbilicus, the arms and dorsum of the hands. The palms, lower body and legs remained dry (Fig. 1A).

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Fig. 1. Case 1. (A) Intense sweating in face and upper body is provoked by apprehension and excitement. (B) Gustatory sweating in responses to chocolate began within minutes in the posterior neck and became quickly more intense. (C) Heat induced sweating: rise in core temperature by 1 °C induced mild sweating in groin, anterior thigh and shin, accompanied by piloerection. (D) Cold induced sweating. At RT 25 °C sweating began within 2 min on forearms, neck, face and chest wall accompanied by piloerection over lower abdomen, groin and thighs. Intensive shivering and dermal vasoconstriction occurred within 10 min. (E) At RT 22 °C sweating was more profuse and was limited to the upper body. Vasoconstriction and shivering were also more intense; core temperature remained unchanged. Plasma noradrenaline and vasopressin rose sharply during cold exposure. (F) After 3 days of clonidine 0.1 mg twice daily sweating was almost totally abolished when tested at RT 19 °C. Minimal sweating was noted above the eyebrows and upper lip. There was no shivering or vasoconstriction.

3.4. Gustatory sweating The patient was placed at RT 28 °C, RH 58% and was given a piece of chocolate cake. Within seconds of the sweet touching the palate she noted a tingling sensation in the posterior neck and shoulders. Two minutes later, pearls of sweat were observed near the posterior hairline and neck. In the following 15 min, sweating became more profuse and more generalized (Fig. 1B). 3.5. Thermoregulatory sweating When mild radiant heat was applied by a heat cradle, to raise the core temperature from 36.8 °C to 37.8 °C, no sweating was observed. The skin temperature increased over the sternum by 2 °C, the thigh by 4 °C, and the index finger by 8 °C, indicating a normal vasodilatation response. She was then given a hot drink and 650 mg of acetyl salicylic acid. Shortly thereafter mild sweating was noted in the pubic area, the medial thighs down to the knees, the lower shin and

dorsum of the foot (Fig. 1C). This was accompanied by piloerection in the groin and the medial thigh. 3.6. Response to intense radiant heat When exposed to direct sun radiation (RT 29 °C, RH 54%) for 20 min profuse sweating was noted in the same areas described above with accompanying piloerection. In addition, sweat pearls were seen over the forehead, eyebrows, nose and upper lip, the lateral anterior chest and periumbilical area, and the mid-posterior chest. During this exposure the sublingual temperature remained unchanged at 37.6 °C. 3.7. Cold-induced sweating Testing was performed on the third experimental day with the patient relaxed and at ease with the procedure. No sweating was observed at RT 27 °C. She was then wheeled into a room of RT 25 °C, RH 56%. Within 2 min, pearls of sweat were noted first over the volar and extensor surface of the forearms,

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then over the forehead and the eyebrows, the upper lip, the axillae and anterior and posterior neck and chest (Fig. 1D). Sweating increased during the next 15 min. Piloerection occurred simultaneously over the lower abdomen, the groin and thighs. Intense shivering began 10 min from the onset of sweating and her nose and hands became pale and cold. The core temperature remained unchanged, while the skin temperature over the chest dropped by 3 °C and the finger temperature by 7 °C. The patient was returned to RT 27 °C for 35 min and covered with blankets. She was then wheeled into a room at RT 22 °C, RH 59%. Profuse sweating developed again within seconds in the same distribution (Fig. 1E). Piloerection and gross shivering occurred; the fingers became white, the nail beds were cyanosed and the finger temperature dropped further by a total of 12 °C. Core temperature, heart rate and blood pressure remained unchanged during the experiment. Because of the severe peripheral vasoconstriction, it was difficult to draw the repeat blood samples. During the exposure to cold, plasma noradrenaline (1474 pmol/L at 27 °C, 8706 pmol/L at 22 °C) and vasopressin (14.5 pg/ml at 27 °C, 47.2 pg/ml at 22 °C) increased to markedly high levels, whereas adrenaline and dopamine levels did not change significantly (Fig. 2). 3.8. Other tests of autonomic function Blood pressure was 120/80 mm Hg supine and in erect position. Heart rate variations were measured in response to deep breathing, Valsalva maneuver, mental arithmetic, and in response to tilting. All values were within the normal range. Resting plasma vasopressin and noradrenaline levels were normal and there was an appropriate rise in noradrenaline on standing (supine 1114 pmol/L; standing 1997 pmol/L) (Fig. 2). A normal triple flare response was noted on testing the axon reflex over the right shoulder blade, the anterior abdominal wall and the anterior thigh. Normal skin wrinkling occurred after prolonged hand immersion in warm water.

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3.9. Effects of treatment 3.9.1. Phenoxybenzamine A trial of the peripheral alpha-adrenoreceptor blocker phenoxybenzamine (10 mg orally twice daily) was abandoned after the fifth dose because of severe orthostatic hypotension. There was little therapeutic benefit. 3.9.2. Clonidine The central alpha-2 adrenoreceptor agonist clonidine (0.1 mg twice daily) abolished all abnormal sweating within 3 days. There were no side effects. When tested at RT 19 °C, RH 60%, minimal sweating was noted over the eyebrows and the upper lip (Fig. 1F). There was no shivering or vasoconstriction. Repeat plasma samples were drawn without difficulty. Resting plasma noradrenaline levels (350 pmol/L) were one third of the pretreatment value. There was no increase with standing or with exposure to cold (Fig. 2). Within 2 weeks, the therapeutic effect lessened but was restored by increasing clonidine to 0.1 mg three times daily. During testing at 6 weeks of treatment the patient showed moderate sweating beginning within 3 to 5 min after exposure to RT 19 °C, RH 67%. This was accompanied by piloerection and shivering. Her fingers were cold and nail beds became cyanosed. Plasma noradrenaline (4830 pmol/L) increased to approximately 50% of the pre-treatment level and was comparable to levels observed in sex- and age-matched controls (2450 pmol/L at 27 °C; 4300 pmol/L at 19 °C). Increase in vasopressin was also less prominent (7.0 pg/ml at 19 °C). Symptom control was again achieved by step-wise dose increases of clonidine to a maximum dose of 0.2 mg three times daily, yet this dose was not tolerated because of sedation, impaired concentration, dry mouth and orthostatic dizziness. The combination of clonidine 0.1 mg four times daily, amitriptyline 50 to 100 mg/day, and increased oral salt intake have resulted in excellent and lasting symptom control for greater than 20 years. Sweating in response to cold, excitement and to sweet gustatory stimuli was almost completely abolished. Medication side effects were tolerable and decreased with time. On reducing the dose, symptoms promptly reappeared. 3.10. Genetic studies

Fig. 2. Changes in plasma noradrenaline with cold exposure. RT 27 °C normal resting plasma noradrenaline and appropriate rise on standing. During cold exposure RT 22 °C excessive rise in plasma noradrenaline to 6 times the baseline level. After clonidine treatment for 1 week suppression of plasma noradrenaline to less than 50% of baseline values; there was no rise with cold exposure. After 6 weeks of clonidine treatment the therapy effect has lessened due to habituation; on exposure to RT 19 °C plasma noradrenaline rises to half of pre-treatment values and mild sweating is observed.

In Case 1, two sequence variants were identified in the CRLF1 gene [encoding the soluble receptor cytokine-like factor 1 (CRLF1)] viz. c.538C N T and c.852G N T. These variants (a nonsense and a missense mutation) are predicted to result in altered gene products, p.Gln180X and p.Trp284Cys. There were no sequence variants in her CLCF1 gene, encoding cardiotrophin-like cytokine factor 1 (CLCF1), which is known to associate with CRLF1 to form a heterodimeric complex CRLF1/CLCF1 [8]. 3.11. Case 2 A man aged 46 years gave a lifelong history of having been unable to sweat when hot, but who had profuse sweating

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on the thorax, face and upper limbs when cold. He felt overheated and faint in hot weather and had to splash himself with water to keep cool. Yet, in cold weather or on entering a cool air-conditioned room, he would sweat from the waist upwards. There were no disturbances of bowel, bladder or sexual function, and salivation and lacrimation were normal. He had experienced feeding difficulties as an infant. His mother, father, sister and three children were alive and unaffected and there was no family history of a similar disorder. There was no parental consanguinity. On physical examination he had protuberant ears set low at right angles to the skull (Fig. 3A). He had mild facial weakness causing a horizontal smile and his palate was high-arched. A thoracolumbar scoliosis and increased lumbar lordosis were present. The elbows were held flexed and could not be fully extended and there was cubitus valgus. The range of flexion and extension of the wrists was reduced. There were flexion contractures of the 3rd, 4th and 5th fingers bilaterally (camptodactyly) and distal phalanges were short (Fig. 3B). The small muscles of the hands and feet were mildly wasted and weak. Tendon reflexes were present. Coordination and sensation were normal. Apart from the skeletal deformities there were no abnormalities on general examination. On review at the age of 72 years, his symptoms of cold-induced sweating were unchanged and there had been no progression of his congenital abnormalities. Mobility was reduced by multilevel degenerative disease of the spine. He declined treatment. The following laboratory studies were normal: full blood count, platelets, serum electrolytes, blood glucose, serum creatinine, blood urea, liver function tests, serum uric acid, cholesterol, triglycerides, thyroid function tests, ECG, serological tests for syphilis, rheumatoid latex test and antinuclear antibodies. Skin biopsies from the left calf and chest showed normal sweat glands. Brain CT and MRI were normal.

3.12. Electromyography and nerve conduction studies Electrophysiological studies were performed according to standard techniques. The right abductor pollicis brevis and abductor digiti minimi muscles were sampled with a concentric needle electrode. There was no spontaneous fibrillation; the pattern was reduced on maximum voluntary effort with units up to 7 mV amplitude firing in relative isolation. Motor conduction velocity (MCV) in the right median nerve was normal [distal latency (DL) 3.8 ms, CV 57 m/s] and reduced in the right ulnar nerve below the elbow [DL 3.1 ms, CV 41 m/s]. On stimulating the right common peroneal nerve at the ankle, an action potential of 200 μV was obtained through a surface electrode over the extensor digitorum brevis muscle; on stimulating at the knee no response was obtained. On stimulating the right index finger, the sensory nerve action potential (SNAP) obtained from the right median nerve at the wrist had a DL of 4.2 ms and amplitude 7 μV, but the right ulnar SNAP could not be obtained. The mixed nerve action potential of the right ulnar nerve, recorded above the elbow on stimulating at the wrist, had a latency of 7.6 ms and amplitude 10 μV. The conclusion was that there was entrapment of the right ulnar nerve at the elbow and possibly compression of the median nerve at the wrist, superimposed on a mild sensorimotor neuropathy. A full set of electrophysiological recordings were repeated at age 72 years confirming the presence of a mild, predominantly sensory neuropathy. 3.13. Sural nerve biopsy The sural nerve biopsy demonstrated a normal density of myelinated fibers (6528 fibers/mm2) with a normal bimodal distribution. Unmyelinated fibers were mildly reduced in density (17,570 fibers/mm2) but there was a normal unimodal distribution.

Fig. 3. Case 1. (A) Characteristic mild dysmorphic facial features with low positioned ears, set at right angles to skull. Elbows could not be extended. (B) Typical flexion contractures of fingers.

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3.14. Sweat tests When the sublingual temperature was raised from 36.3 °C to 36.9 °C no sweating occurred on the trunk but there was some sweating on the knees and thighs. The patient became distressed and tachypnoeic. On lowering the temperature from 37.1 °C to 35.5 °C with a controlled hypothermic blanket, profuse sweating occurred on the upper part of the trunk and upper limbs, accompanied by shivering and piloerection. 3.15. Other tests of autonomic function The supine blood pressure was 150/90 mm Hg and did not change significantly on standing or with tilting. Response to the Valsalva maneuver was normal when the full hemodynamic responses were recorded with an intra-arterial catheter. Valsalva ratio was 1.7. Baroreflex sensitivity was tested by measuring the heart rate response to blood pressure changes induced with intravenous phenylephrine and glyceryl trinitrate. The responses were well within the normal range. The plasma noradrenaline resting level was 3600 pmol/L and rose on standing to 5500 pmol/L and on isometric contraction to 6600 pmol/L. No specific treatment was given. 3.16. Genetic studies Case 2 was compound heterozygous for a CLCF1 stop mutation (c.321C N A, p.Tyr107X) and a missense mutation (c.590G N T, p.Arg197Leu), while no sequence variants were identified in 140 chromosomes from healthy controls. He was also heterozygous for a sequence variant in the CRLF1 gene (c.73_75delCTG), as were 29 of 93 normal blood donors. This CRLF1 variant most likely represents a common polymorphism (allele frequency 0.18) with no known clinical consequences. No other family members were available for genetic testing. 4. Discussion We report the clinical and genetic findings in two unrelated patients, suffering from ‘cold-induced sweating syndrome’ (CISS [MIM #272430]), a rare autosomal recessive disorder, first described by Sohar et al. [1]. Paradoxically, both patients exhibited profuse sweating in the upper body on exposure to cold ambient temperatures. When the room temperature was lowered to 25 °C (Case 1) or the sublingual temperature to 35.5 °C (Case 2), intense sweating occurred on the upper limbs, the anterior and posterior aspects of the trunk to the waist, the forehead, eyebrows and the upper lip. In contrast, both patients had very little sweating and only in the lower limbs when the body temperature was raised above 37 °C. In keeping with the previous descriptions of CISS, both individuals also had characteristic dysmorphic facial features, including high-arched palate and nasal speech; and in Case 2

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mild facial weakness causing a poor horizontal smile, and protuberant low set ears. Moreover, both had a range of skeletal deformities. Knappskog et al. [3] had made similar observations in two Norwegian brothers, who in addition to cold-induced sweating also had very prominent skeletal deformities, including progressive and severe kyphoscoliosis, elbow and wrist contractures, short hands with pronounced clinodactyly and tapering of the fingers. Their facial expression was diminished due to facial muscle weakness, and they had difficulty in fully opening their mouth. Both brothers reportedly had encountered life-threatening feeding problems in the neonatal period as they did not suckle spontaneously, and demonstrated extreme lack of interest in food. Thus, they required a lengthy hospital admission for assisted feeding via a naso-gastric tube and later via a special sucking device. Feeding difficulties were also reported for both our patients, although they seemed to have been less severe and more readily overcome. Nonetheless, the problem appears to be characteristic feature. Given the phenotypic similarities between the Norwegian patients and the Israeli siblings described earlier, Knappskog et al. [3] postulated autosomal recessive inheritance. This was confirmed by their observation that the Norwegian and Israeli siblings were homozygous for different mutations in the CRLF1 gene. This data suggested that CISS might be caused by the impaired function of cytokine receptor-like factor 1 (CRLF1), a soluble cytokine receptor which specifically associates with cardiotrophin-like cytokine factor 1 (CLCF1) [8]. The frameshifting mutation encountered in the Norwegian brothers predicted a severely truncated and non functional CRLF1 gene product, possibly accounting for the more severe phenotype. DNA sequencing revealed that Case 1 was compound heterozygous for two different novel CRLF1 mutations, thus corroborating the CISS diagnosis. Yet in Case 2, no sequence variants were found in this gene, apart from heterozygosity for a seemingly normal CRLF1 variant (c.73_75delCTG) — a common polymorphism in the Norwegian population. Since CLCF1 must complex with CRLF1 to be secreted from the cell in order to act as ligand to the ciliary neurotrophic factor receptor (CNTFR), a deficiency in CLCF1 was predicted to produce a similar CISS phenotype. In keeping with this hypothesis, Case 2 showed compound heterozygosity for two different CLCF1 mutations, not present in 70 normal controls. Thus, we demonstrate for the first time that CISS is a genetically heterogeneous disorder. To avoid confusion, and in accordance with the HUGO nomenclature, the two disorders are called CISS1 (CRLF1 deficiency) and CISS2 (CLCF1 deficiency). Although functional analyses of the CRLF1 mutated proteins from CISS1 patients have not yet been performed, studies of the CLCF1 mutated protein of Case 2 showed complete loss of function because of its inability of binding to the CNTF receptor [9]. CLCF1 is a member of the interleukin-6 family of cytokines. It is expressed in a number of tissues and supports the survival of developing motor neurons in vitro [8] To be

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Table 1 Clinical features of reported cases of cold-induced sweating syndrome Cases

Canadian

Australian

Norwegian

Israeli

Number

1

1

2

2

Age of onset Early feeding difficulties Facial appearance Palate Ears

Early childhood Yes

Early childhood Yes

Infancy Yes

Infancy No

Narrow face High arched Low set, posteriorly rotated Mild thoraco-lumbar scoliosis Flexion deformity, cubitus valgus No abnormality

Horizontal smile; mild facial weakness High arched Low set, laterally rotated

Facial weakness High arched Low set ears

Lumbar lordosis and spondylosis, thoraco-lumbar scoliosis Flexion deformity, cubitus valgus Limited flexion and extension

Severe progressive kyphoscoliosis Limited supination and extension No abnormality described

Poorly developed nasal bridge High arched No abnormality described Slight kyphoscoliosis

Flexion deformity 3rd and 4th fingers No abnormality

Flexion deformity 3rd to 5th fingers. Tapered distal phalanges Weakness, wasting of intrinsic muscles

Clinodactyly. Thick and foreshortened fingers No abnormality described

Syndactyly 2nd and 3rd toes No

Wasted intrinsic muscles, clawed and webbed 2nd and 3rd toes Mild sensorimotor neuropathy

CRLF1 mutations Q180X + W284C

CLCF1 mutations Y107X + R197L

Flat feet, short toes syndactyly 2nd and 3rd toes Mild sensorimotor neuropathy CRLF1 mutations V282fs homozygous

Spine Elbows Wrists Fingers Hand muscles Feet Peripheral neuropathy Genetic abnormality

secreted from the cell CLCF1 interacts with CRLF1 to form a stable CLCF1/CRLF1 complex which then acts as functional ligand to the membrane-bound CNTFR [8,10]. The latter is widely expressed in PNS and CNS neurons during embryonic life [11]. The tripartite CNTFR constitutes a ligand binding domain, CNTFR, and two signal transducer subunits, IL6ST [(interleukin 6 signal transducer) or gp(glycoprotein)130] and leukaemia inhibitory factor receptor (LIFR). Binding of CLCF1/CRLF1 to the CNTFR leads to the dimerization of gp130/LIFR, which in turn induces signaling events, including activation of the Janus kinase 1 (JAK1)/STAT3 pathways [12]. It has been shown that mice lacking the CNTFR exhibit profound motor neuron deficits at birth and die perinatally [13] while mice and humans containing non-functioning CNTF, another ligand to CNTFR, appear remarkably normal [13–15]. However, CLCF1-deficient mice (NR6−/− mice) died shortly after birth due to lack of suckling [16]. Such mice also exhibited a significant reduction in facial and lumbar motor neurons, while hypoglossal, brachial and thoracic motor neurons were normal. Sensory neurons in the dorsal root ganglia (DRG) were also normal in number [17]. CLCF1 and CRLF1 mRNAs were shown to be expressed in embryonic mice in various brain and spinal cord regions and in muscle [16–18]. The widespread expression in both neuronal and mesenchymal tissues may explain the multiple dysmorphic features observed in CISS patients. Moreover, suckling and feeding difficulties in observed in CISS patients during the neonatal period are reminiscent of those observed in mice. The clinical features of the Canadian, Australian, Norwegian and Israeli CISS cases are compared (Table 1). Their phenotype was remarkably similar. Precarious feeding

Limited extension No abnormality described No abnormality described No abnormality described Hammer toes Not described CRLF1 mutations R81H; L374R homozygous

difficulty during infancy and the development of severe and progressive kyphoscoliosis was a prominent feature in the two Norwegian brothers, who presumably harbor a CRFL null mutation, and was present but less severe in the here reported cases. Unlike the other patients, the sisters from Israel had no reported abnormalities of their fingers. Both the Australian case (CISS2) and the severely affected Norweigian case (CISS1) had signs of a mild sensorimotor neuropathy. This was not present in the milder CISS1 cases. Extensive autonomic function studies were undertaken (Table 2) and revealed no abnormality in blood pressure or heart rate control, resting plasma adrenaline, noradrenaline and vasopressin or plasma noradrenaline in response to change in posture. Tests of sympathetic efferent functions were also normal, including sympathetic skin response, flare response and axon reflex. Abnormalities concerned only the regulation of sudomotor functions, whereby both individuals experienced the rapid onset of excessive sweating in the face, arms and upper body on exposure to cold ambient temperature (b25 °C in Case 1), while showing very little sweating in the heat and mainly in the legs. The precise mechanisms underlying this paradoxical sweat response are not yet known. Sohar et al. [1] concluded that there was possibly a peripheral mechanism operative in their cases, since abnormal sweating was abolished by oral atropine sulphate, but this finding would be expected with both central and peripheral causes of excessive sweating. In Case 1, we observed sweating, albeit less intense, in the same upper body distribution in response to apprehension and to gustatory stimuli. Moreover, in this patient we also demonstrated during the cold-induced sweating a massive release of

A.F. Hahn et al. / Journal of the Neurological Sciences 250 (2006) 62–70 Table 2 Tests of autonomic function Tests

Case Case Region tested 1 2

BP response to standing and tilting HR response to standing and tilting HR variation with respiration

N

N

N

N

N

–

Baroreflex sensitivity

–

N

HR response to Valsalva maneuver BP response to Valsalva maneuver Valsalva ratio

N

N

–

N

N

N

N N

N N

N N

– N

Resting plasma noradrenaline Plasma noradrenaline response to change in posture Resting vasopressin Axon reflex

Afferent and efferent limbs of reflex arc Afferent and efferent limbs of reflex arc Vagal afferent and efferent limbs of reflex arc Vagal afferent and efferent limbs of reflex arc Afferent and efferent limbs of reflex arc Afferent and efferent limbs of reflex arc Afferent and efferent limbs of reflex arc Sympathetic efferents Sympathetic efferents Sympathetic efferents Postganglionic sympathetic efferents

noradrenaline and of vasopressin (Fig. 2). This response was completely suppressed by oral clonidine, and in parallel the cold-induced sweating and the gustatory sweating were almost completely abolished. The excellent therapy effect of clonidine has persisted. Given these observations and in view of the rapidity of onset of sweating in response to anxiety, gustatory inputs, and cold we have favored a central, possibly a hypothalamic site of dysfunction, yet no structural abnormalities were noted in the patients' brain MRIs. Spells of hyperhidrosis and hypothermia have been described in a few patients with “Shapiro's syndrome” in association with anatomic callosal or hypothalamic abnormalities [2,19,20]. In some of these cases, high plasma levels of noradrenaline were measured during the spells, which were effectively reduced by clonidine [21,22]. However, unlike in CISS, these patients had appropriate physiological responses to environmental temperatures. Our two patients were distinctly different from those with Shapiro syndrome, since their episodes of sweating were always provoked by cooling. Sweating was profuse and occurred only regionally in the upper part of the body. Interestingly, within minutes from onset of sweating on exposure to cold, both patients also exhibited the appropriate regulatory responses for heat preservation, such as vasoconstriction and massive shivering. Their core temperature was thus maintained, while the skin temperature dropped sharply. Gain of sweating was markedly elevated; it increased over time, since evaporation of sweat lead to further skin cooling. Sweating in response to cold exposure was so prominent, that both individuals had reported not to be able to sweat in the heat. Yet, upon testing them with intense directed heat application, both patients showed mild sweating, which occurred first in the legs and groin area and subsequently in the face and chest. This response, albeit exhibiting a very low gain, corresponded to the

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normal pattern of recruitment of sweating [23]. The patients also experienced piloerection in the same distribution. This paradoxical response of simultaneous sweating and piloerection indicated a heightened activity in sympathetic skin nerves, and the parallel activation of sudomotor and piloerector fibers [24]. Thus, the unusual sweat responses in our two patients might be due to an excessive and centrally regulated release of catecholamines in response to physiological triggers, resulting in the simultaneous activation of the dual sympathetic responses in the periphery. The anterior hypothalamus and preoptic area (AH/POA) have a central role in orchestrating thermoregulatory responses [25]. The region contains warm- and cold-sensitive neurons, which respond to local temperature, acting as central thermosensors [26]. The AH/POA also receives input from various cortical regions [27], notably the posterior insula [28], and from afferent projections of peripheral thermoreceptive pathways. Recent studies of thermoregulation have placed greater emphasis on ascending thermal signals for the activation of central thermoregulatory mechanisms. These arise from the peripheral thermosensors, namely from thermoreceptors (TRP) in skin and in subcutaneous tissues [29]. The abnormal sweat responses in CISS patients, may result from alterations in the temperature signals triggering sudation, provided by sensory neurons to the thermal integrators located in the AH/POA. Such observations would be in accord with the very rapid onset of cold-induced sweating in our two patients, which occurred in parallel with a sharp decrease in the skin temperature, while the core temperature remained unchanged. Advances have occurred in the molecular characterization of peripheral thermal sensors, a subset of transient receptor potential ion channels (temperature activated TRPs) that are present in specialized DRG sensory neurons and in epithelial cells [30,31]. There is preliminary evidence from the study of mice suggesting that the CLCF1/CRFL1 composite cytokine plays a role in these neuronal differentiations (Gauchat, personal communication). Moreover, recent studies have demonstrated that the postnatally occurring switch of the sweat gland innervating sympathetic neurons, from an adrenergic to cholinergic differentiation, is mediated by gp130 signaling [31], and may possibly also involve the CLCF1/ CRFL1 cytokine complex. Thus, it is probable that in CISS peripheral sudomotor functions are also affected. The various mechanisms might contribute to the observed unusual patterns of cold- and heat-induced sweating. Clonidine, an agonist of central presynaptic alpha2adrenoreceptors, induces feedback inhibition of synaptic noradrenaline release, thereby blocking central sympathetic neural activity [32]. On exposure to 22 °C, the plasma noradrenaline levels of patient 1 had increased to greater than six times of baseline values but after only 1 week of oral clonidine plasma noradrenaline was less than half of baseline. It also did not rise on cold exposure (Fig. 2) and the patient had become completely asymptomatic. The beneficial effects of clonidine lessened within a few weeks due to habituation and dose increases were associated with intolerable sedation, dry

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mouth and postural hypotension. Excellent and lasting symptom control was finally achieved by combining low dose clonidine with amitriptyline, which reduces central Noradrenaline reuptake and exerts anticholinergic effects. The drug combination has been beneficial for nearly 20 years and has allowed the patient to lead a normal life. This pharmacological regime may be considered in future cases. Acknowledgments The authors thank the patients for their cooperation, Dr. P.A. Low for helpful advice regarding options of treatment for this condition, Dr. N.W. Kasting for carrying out measurements of vasopressin, Drs. P.M. Satchell and R.R Tuck for assistance with the autonomic tests in Case 2, and Dr. Hugues Gascan for providing data on the absence of sequence variants in the CLCF1 gene in 70 controls and for sharing his results of functional studies of the mutated CLCF1 protein ahead of print. We are grateful for skilful technical assistance of Ms. J.S. Bringsli and I.B. Tjelflaat. References [1] Sohar E, Shoenfeld Y, Udassin R, Magazanik A, Revach M. Coldinduced profuse sweating on back and chest: a new genetic entity? Lancet 1978;2:1073–4. [2] Klein CJ, Silber MH, Halliwill JR, Schreiner SA, Suarez GA, Low PA. Basal forebrain malformation with hyperhidrosis and hypothermia: variant of Shapiro's syndrome. Neurology 2001;56:254–6. [3] Knappskog PM, Majewski J, Livneh A, Nilsen PTE, Bringsli JS, Ott J, et al. Cold-induced sweating syndrome is caused by mutations in the CRFL1 gene. Am J Hum Genet 2003;72:375–83. [4] Hahn A, McLeod JG, Boman H. Cold-induced sweating syndrome — a report of two cases. J Neurol Sci 2005;238(Suppl 1):79–80 Abstract. [5] McLeod JG, Tuck RR. Disorders of the autonomic system: Part 2. Investigation and treatment. Ann Neurol 1987;21:519–29. [6] Low PA. Quantitation of autonomic function. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF, editors. Peripheral Neuropathy. 3rd Edition. Philadelphia: WB Saunders; 1993. p. 729–45. [7] Dyck PJ, Gianni C, Lais A. Pathologic alterations in nerves. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Podulso JF, editors. Peripheral Neuropathy. 3rd Edition. Philadelphia: WB Saunders; 1993. p. 514–95. [8] Elson GCA, Lelièvre E, Guillet C, et al. CLF associates with CLC to form a functional heteromeric ligand for CNTF receptor complex. Nat Neurosci 2000;3:867–72. [9] Rousseau F, Gauchat J-F, McLeod JG. Inactivation of cardiotrophinlike cytokine, a second ligand for CNTF receptor, leads to cold induced sweating syndrome in a patient. PNAS 2006;103:10068–73. [10] Lelièvre E, Plun-Favreau H, Chevalier S, et al. Signaling pathways recruited by the cardiotrophin-like cytokine/cytokine-like factor-1 composite cytokine. J Biol Chem 2001;276:22476–84. [11] Ip NY, McClain J, Barrezueta NX, et al. The α component of the CNTF receptor is required for signaling and defines potential CNTF targets in the adult and during development. Neuron 1993;10:89–102.

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