Successful treatment of cold-induced sweating in Crisponi syndrome and its possible mechanism of action Jana Herholz 1 , Laura Crisponi 2 , Birendra N Mallick 3 , Frank Rutsch 1 1 Department of General Pediatics, Münster University Children's Hospital, Münster, Germany. 2 Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari, Italy. 3 School of Life Sciences, Jawaharlal Nehru University, New Delhi, India. Correspondence to: rutschf@ukmuenster.de doi: 10.1111/j.1469-8749.2010.03630.x SIR–Crisponi syndrome (MIM #601378) is a rare severe infantile autosomal recessive disorder characterized by parox- ysmal contractions of the facial muscles, hyperthermia, feeding difficulties, and camptodactyly. 1 Hyperthermia frequently leads to death within the first months of life, whereas the rare surviving patients develop scoliosis, psychomotor retardation, and cold-induced sweating. 2 The syndrome is caused by muta- tions in the cytokine receptor-like factor 1 (CRLF1) gene, 2,3 mutations of which have also been associated with cold- induced sweating syndrome (CISS; MIM #272430), 4 and it can be hypothesized that these two syndromes reflect different manifestations of the same entity. 2,3 We present two Turkish siblings with Crisponi syndrome, in whom cold-induced sweating associated with excessive noradrenaline release was effectively treated with moxonidine, a centrally acting imadoz- oline receptor agonist. The parents consented to the publica- tion of this report. The male patient was born as the third child of consanguin- eous parents originating from Eastern Turkey. 2 The first child of the family died 21 hours after birth of respiratory distress; four other siblings are healthy. The patient was born at 40 weeks’ gestation after an uneventful pregnancy, with Apgar scores of 10 ⁄ 10 at 5 and 10 minutes respectively. On initial examination, camptodactyly of the 4th and 5th fingers of both hands was noted. Within the first few weeks of life, he developed recurrent hyperthermia with core tempera- tures up to 40°C. He exhibited an increased flexion tone of the extremities and truncal hypotonia as well as paroxysmal con- tractions of the facial muscles. Because of sucking and swal- lowing difficulties he was fed through a nasogastric tube during the first 10 months of life. Metabolic screening was normal, as was brain sonography and electroencephalography at 1 year of age. The karyotype was 46, XY. During his second year of life, hyperthermia and feeding difficulties resolved. He learned to walk at the age of 18 months. At 10 years of age he first complained of ‘feeling cold on the back and on the hands’ and of spontaneous sweat- ing attacks on different occasions. At the age of 14 years profuse sweating of the upper part of the body occurred at room temperature. He was found to sweat intensely and to feel uncomfortable in cold rooms and to feel well at higher ambient temperatures. The female patient is the younger sister of case 1. She was born at 41 weeks’ gestation. In early infancy, she had feeding difficulties and presented almost identical symptoms and an almost identical clinical course to her elder brother. She was noted to cry with a compressed mouth and increased saliva- tion. She developed a thoracolumbal scoliosis and increased sweating at low ambient temperatures at 7 years of age. She felt more comfortable during hot summer days. Because of increasing scoliosis a dorsal instrumentation was placed surgically. At the age of 13 years, the diagnosis of Crisponi syndrome was established. In both patients the mutation c.708–709delCCinsT was found on both alleles of CRLF1, resulting in the frame shift p.Pro238ArgfsX6. 2 To visualize areas of sweatening in both probands, an iodine solution (Jodi puri 1.5, Olei ricini 10.0, Spiritus 96% 90.0) was applied before covering the skin with potato starch powder. A violet discoloration of the covered areas was considered positive for sweating. 5 In both siblings, at 27°C ambient temperature, only very mild sweating was noted. However, while sitting undressed at 19°C, within 2 minutes intense sweating occurred, starting on the lower arms and spreading to the neck, upper back, shoulders, and upper arms accompanied by piloerection. After 5 to 7 minutes, the entire upper part of the body was sweating (Fig. 1a). Body core temperature dropped by 1°C and heart rate increased by about 20 beats per minute. In the male a 27-fold rise (Fig. 1c), while in the female a 7-fold rise in plasma noradrenaline (NA) levels was registered (Fig. 1e). This increase was excessively greater than the reaction to standing up from a supine position (Fig. 1c,e). In contrast, in both patients, the changes in adrenaline levels were stronger in response to standing than in response to cold exposure (Fig. 1d,f). Both probands were treated with the central a 2 -adrenore- ceptor agonist clonidine with a maximum dose of 3lg ⁄ kg body weight per day, which resulted in a dramatic decrease of cold- induced sweating within 3 days. Because both siblings felt exceedingly tired during 2 years of treatment with clonidine, the medication was changed to moxonidine with a maximum dose of 6lg ⁄ (kg ⁄ d), which was better tolerated. In the female, 14 months after the start of moxonidine only very mild sweating was seen at 19°C ambient temperature on the upper lip and in the elbow flexures (Fig. 1b). Under moxo- nidine treatment, adrenaline baseline levels were lower than before (Fig. 1f), however, the noradrenaline baseline level was slightly higher than before (Fig. 1e). Conspicuously, there was no significant increase of catecholamine levels in response to cold exposure under treatment; the plasma adrenaline level rose to 132%, whereas the noradrenaline level even dropped to 33% of the baseline level (Fig. 1e,f). 494 ª The Authors. Journal compilation ª Mac Keith Press 2010 DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY CLINICAL LETTER