Cold-induced sweating syndrome type 1 (CISS1) is a rare disorder characterized by profuse sweating in a cold environment, determined by mutations in cytokine receptor–like factor 1 (CRLF1).1 Its pathogenesis is not fully understood. It has been demonstrated in vitro that CRLF1 may be involved in inducing differentiation from a noradrenergic to a cholinergic transmitter phenotype. During development, catecholaminergic and cholinergic neurotransmission is required for the induction of secretory function, whereas cholinergic transmission becomes crucial for the maintenance of the secretory responsiveness.2 The abnormal sweat response in CISS1 could be also related to alterations in temperature signals acting on hypothalamus and preoptic areas.1
We report clinical, molecular, skin biopsy, and temperature monitoring data of an Italian boy with CISS1.
Case report.
A 16-year-old boy had come to our observation at 1 year of age. His parents were healthy and unrelated. A brother, with facial dysmorphisms and hypotonia, had died at age 3 months from bronchopulmonary infection. Our patient was hypotonic at birth and experienced severe feeding difficulties. He had elongated face, high-arched palate, weak cry, large pinnae, short hands, tapering fingers, clinodactyly, and reduced tendon reflexes. Concentric needle EMG, nerve conduction velocity (NCV) studies (ulnar, median, peroneal, tibial, and sural nerves), and repetitive nerve stimulation testing excluded a neuromuscular disease. A vastus lateralis muscle biopsy revealed type 2 fiber atrophy.
In the following years, feeding difficulties and hypotonia improved. He had deficient sweating in warm environment with heat intolerance, hyperpyrexia, and abundant sweating on his back and hands after exposure to cold or during stressful conditions. At age 13 years, a dorsal kyphoscoliosis was evident. Brain MRI, EMG, and NCV had normal results. Sympathetic skin responses3 recorded from hands and feet were absent and CISS1 was suspected.
Molecular study.
DNA from the patient, his healthy brother, and parents was processed as previously described.4 The proband was heterozygous for a paternal c.935 G>A missense mutation (p.Arg312His). Array CGH analysis identified a maternal deletion between 19 kb and 39 kb on chromosome 19 encompassing exons 6–9 of the CRLF1 and the entire gene C19orf60, confirmed by sequencing DNA segments for single nucleotide polymorphisms and testing for microsatellite markers in this region.
Sweating evaluation.
Thermoregulatory sweat test5 suggested generalized anhidrosis. The boy showed paradoxically hyperhidrosis in the upper trunk, neck, shoulders, and armpits in a cooled room. Silastic imprint test showed few scattered sweat droplets on thighs and on the back of his hands and feet.
Skin biopsy.
Cutaneous innervation in hyperhidrotic (fingertip and shoulder) and anhidrotic (thigh) skin was studied.6 Protein gene product 9.5 (PGP)-ir sudomotor innervation appeared overall poor and well-organized [figure, A(b)] in all samples. No vasointestinal peptide (VIP)-ir nerves were observed around sweat glands [figure, A(d)] and other annexes while dopamine β-hydroxylase (DbH)-ir sudomotor fibers were unusually abundant in skin samples from shoulder [figure, A(f)], very few in the fingertip, and absent in thighs. Epidermal nerve fiber density, Meissner corpuscles, and intrapapillary myelinated fibers were normal.
(A) Skin biopsy. Confocal micrographs of sweat glands from a healthy subject (a, c, and e) and from our patient (b, d, and f): upper arm skin biopsy. Sudomotor innervation is complex as shown by protein gene product 9.5 (PGP) (a) and vasointestinal peptide (VIP) (c) immunoreactivity. Few dopamine β-hydroxylase (DbH)–immunoreactive fibers are present and mainly located around the vascular component of the gland (e). In the patient, sudomotor plexus appears poor with PGP (b) and absent with VIP (d) in all skin samples (hyperhidrotic and anhidrotic areas). An abundance of DbH fibers encircling sweat tubules is present (f). In c and d, gland structure is visualized using ULEX Europaeus agglutinin A. Bar equals 100 μm in a to d and 50 μm in e and f. (B) 24-hour profile of body core temperature (Bct°) in our patient. The increase of Bct° started at the beginning of both episodes of hyperhidrosis. H: hyperhidrosis; first episode from 1:50 to 2:50 pm and second episode from 9 to 10 pm. Bct° showed different patterns for 1 hour following the hyperhidrotic episodes, resulting in a change in body temperature of +0.4°C and −0.64°C. The black bar on the x axis indicates the dark period from 11 pm to 7 am. (C) Chronogram of the analysis of the circadian rhythm of Bct° in a control subject. (D) Chronogram of the analysis of Bct° in our patient. The black bar on the x axis indicates the dark period from 11 pm to 7 am.
Body temperature 24-hour study.
Body core temperature (Bct°) was evaluated by continuously monitoring rectal temperature for 24 hours by means of a Mini-logger™ portable device. Circadian fluctuation, rhythm, midline estimating statistic of rhythm (MESOR), amplitude, and acrophase were analyzed according to the single cosinor method.7 The 24-hour pattern of Bct° showed a minimal difference between mean diurnal and nocturnal values with blunted physiologic nocturnal fall. A significant 24-hour Bct° fluctuation with normal MESOR, reduced amplitude, and slightly advanced acrophase was found (figure, D). Two episodes of hyperhidrosis were recorded (figure, B).
Discussion.
We report an Italian patient with CISS1 with a severe phenotype due to compound heterozygosity for 2 CRLF1mutations. The predominant muscle involvement and feeding problems occurring in infancy mimicked a muscular disease.
The peculiar pattern of sweat gland innervation observed, with a generalized lack of cholinergic fibers and a rich adrenergic supply, could be the morphologic in vivo evidence of a failed CRLF1-dependent switch from adrenergic to cholinergic sweat gland innervation and may explain the inverse sweating response in CISS1. A length-dependent degeneration of the abnormal adrenergic sudomotor fibers could account for the limitation of this pattern to the upper body. The failed adrenergic-cholinergic switch could also explain bone deformities, muscular symptoms, and the high variability in clinical presentation at different stages of life, as cholinergic sympathetic neurons innervate also the periosteum, the connective tissue covering the bone, and the skeletal muscle vasculature.2
The variations in Bct° observed in our patient at the beginning of hyperhidrosis suggest that a central dysfunction may contribute to the thermoregulatory failure in CISS1.
Footnotes
Disclosure: Dr. Di Leo, Dr. Nolano, Dr. Boman, Dr. Pierangeli, Dr. Provitera, Dr. Knappskog, and Dr. Cortelli report no disclosures. Dr. Vita serves on the Executive Board of the World Muscle Society. Dr. Rodolico reports no disclosures.
- Received January 31, 2010.
- Accepted May 17, 2010.
- Copyright © 2010 by AAN Enterprises, Inc.
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