Australas J. Dermatol 1992; 33: 103-107
CONGENITAL SENSORY NEUROPATHY WITH ANHIDROSIS (HEREDITARY SENSORY NEUROPATHY TYPE IV) J. HATZIS, K. GOURGIOTOU, D. KOUMELAS, G. MAKARONIS, A . VARHLZIDIS AND J. STRATIGOS
Ioannina and Athens, Greece SUMMARY
Hereditary sensory neuropathies comprise a group of rare childhood diseases which are classified into four types. We present a Greek boy 11 years old with hereditary sensory neuropathy type IV (congenital sensory neuropathy with anhidrosis) whom we have followed up and studied during the last seven years. Our patient presented for the first time with recurrent hyperthermic episodes without sweating, and lack of pain sensation from the first months of life. Insensitivity to pain and thermal stimuli had resulted in burns on the extremities and self-mutilation of the tongue, lips and fingertips. When he was five and seven years old respectively he had two painless fractures of the ankles which led to insoluble orthopedic problems. He also suffered from mental retardation, which was obvious from his first years of life. Sweat gland investigations showed significant hypohidrosis or anhidrosis although the sweat glands were normal microscopically. Hereditary sensory neuropathy type IV, although rare, is important for dermatologists because it must be differentiated from other anhidrotic syndromes, and in view of the poor prognosis of the condition. Key words: congenital sensory neuropathy, pain, temperature, sweat, injuries, fractures, mental retardation. INTRODUCTION
Congenital sensory neuropathies make up a group of rare diseases of childhood characterised by insensitivity to pain and other neurologic deficits. The impaired recognition of pain is a handicap leading to extensive self-mutilation and traumatic amputation. These diseases are classified into four types.' In this study a Greek boy suffering from congenital sensory neuropathy with anhidrosis is presented. CASE REPORT
G.D., a Greek boy, was examined for the first time in "A. Sygros" Hospital in 1982 when he Presented at the First Congress of the European Academy of Dermatology and Venereology, September 1989, Firenze. J. Hatzis MD, Department of Skin and Venereal Diseases, University of Ioannina. K. Gourgiotou A. Varelzidis, J. Stratigos Department of Dermatology, "A. Sygros" Hospital, University of Athens. D. Koumelas, G. Makaronis Second Department of Pediatrics, "Agia Sofia" Hospital, Athens. Address for correspondence: John Hatzis, MD, Department of Skin and Venereal Diseases, University of Ioannina, 45110 Ioannina, Greece.
was four years old, suffering from anhidrosis, febrile episodes and anaesthesia to pain or thermal stimuli. G.D. was born in May 1978 and was the first child of healthy non-consanguineous parents. The patient's gestation (37 weeks) and delivery were normal with weight at birth 3.3 kg. His younger sister and other family members were also normal. During the first months of life the patient suffered from episodes of unexplained fever, without sweating. It was also known that he did not sweat under normal conditions. The patient also showed no response to painful or thermal stimuli. This resulted in wounds or burns, especially on the extremities, as well as on the lips and tongue, after appearance of his first tooth (7 months). The patient presented delayed motor and mental development. He walked at the age of two and he started speaking at 3.5 years of age, with a poor vocabulary. Now he is 11 years old and attends the 3rd grade of elementary school. Physical examination at the age of four years revealed a cooperative, small and thin child (Fig. 1). His tongue was short and self-mutilated. The teeth of the upper jaw were normal, whereas on the lower jaw we found only three teeth. This was
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J. HATZIS, K. GOURGIOTOU, D. KOUMELAS, G. MAKARONIS, A. VARELZIDIS & J. STRATIGOS
FIGURE 2 ^ r h e patient at seven years of age, walking with the help of a leg brace, because of abnormal porosis of a bouc fracture.
FIGURE 1—The patient at four years of age.
due to the fact that the milk teeth of the lower jaw had been lost early, but the permanent teeth which were intact (confirmed by panoramic Xray) had not yet appeared. The hair and nails were normal. His skin was dry. He did not respond to painful stimuli such as needle prick over the face, trunk and extremities. A skin biopsy was taken without local anaesthesia. Also, pressure applied to the testicles, Achilles tendon area and bones did not produce any response. He was unable to distinguish between hot and cold. The deep tendon reflexes were depressed or absent. Muscular strength was normal. Tactile sensation was universally present. The corneal reflex was normal. The cranial nerves were intact. Lacrimation and salivary function were normal. Blood pressure was 110/70 mm Hg. At the age of five and seven years the patient suffered from painless bone fractures in both legs. Recovery was delayed and abnormal. Thus, he walked only with the help of a leg brace for a long period of time (Fig. 2).
FIGURE
3^
atient at seven years of age showing his selfmutilated tongue.
Repeated self-mutilation of the tongue resulted in an extreme shortening of the tongue which he could not move out of the mouth (Fig. 3). He suffered very often from erysipelas or impetigo because of the repeated wounds on the extremities. 104
CONGENITAL SENSORY NEUROPATHY WITH ANHIDROSIS LABORATORY INVESTIGATIONS
Haemoglobin, white blood cells, glucose, blood urea, serum electrolytes, immunoglobulins and proteins were all normal. The sedimentation rate was 20mm/hr. Urinalysis was normal. Electroencephalogram was normal. Electromyography and electroneurography were normal. Computerised axial tomography of the brain was normal. Prick testing with histamine solution 1:1000 produced only the expected wheal, but not the axonal flare. Skin biopsy from the anterior surface of the right thigh showed anatomically normal sweat glands. The secretory coils consisted of short, well stained secretory cells (Fig. 4). The nerves of the skin were not studied. Sweating was detected by the plastic impression technique in combination with the starch iodine method^ as follows: the area to be studied was painted with a 5% non-alcoholic iodine solution and after about one minute, when the area had dried well, starch powder was applied in a very
thin layer with the aid of cotton wool. Immediately after that, the silicone material ("Silaplast", Dental Karl Humber Kg., 75 Karlsruhe, W, Germany) was mixed well with a few drops of catalyst, and the area for examination was covered with it. After about 20 min, on removing the imprint, the sweat droplet could be seen and studied on the white area of silicone material, showing a circular or oval shape with a deep violet stain. The sweating tests showed: a) Sweating on palms (emotional sweating area') and torso, forehead, right forearm and right thigh (thermoregulatory sweating areas^ under a radiant heater for an hour" was completely absent. b) indradermal injection of 0.1 ml prostigmine solution 1:10.000 on the anterior surface of the thigh did not produce any sweat response. c) indradermal injection of 0.1 ml of metacholine 1:10.000 on the anterior surface on the thigh resulted in the functioning of 10 glands per
FIGURE 4—Sweat glands anatomically normal.
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J. HATZIS, K. GOURGIOTOU, D. KOUMELAS, G. MAKARONIS, A . VARELZIDIS & J. STRATIGOS
d) iontophoresis with 1% solution of acetylcholine resulted in the functioning of 3 glands per lcm^ e) after repeating iontophoresis with acetyl-' choline chloride daily in the same site (thigh) for nine days (sweat gland training'^) we observed that the functioning sweat glands increased from 3 to 10 per lcm^ Ambient Laboratory conditions: Temperature = IQ-ll'C, R.H. = 55-60%. Apocrine sweat glands were not studied because the patient was examined by us before puberty. DISCUSSION
Congenital sensory neuropathy with anhidrosis (CSNA, type IV) is a rare childhood syndrome characterised by the universal absence of reaction to painful stimuli, impaired perception of thermal stimuli, absence of sweating despite the presence of normal sweat glands, and recurrent febrile episodes without sweating. Also mental retardation, self-mutilation of the tongue, wounds and burns on the extremities, and painless bone fractures are very common features in these patients.'"'*'""' Our patient presented with all typical clinical and laboratory symptoms of congenital sensory neuropathy with anhidrosis (hereditary sensory neuropathy, type IV). This rare childhood syndrome (literature search found 22 cases, 15 boys and 7 girls") must be differentiated from other types of sensory neuropathies. Table 1 shows the main diagnostic points of the sensory neuropathies. Sural nerve biopsies have revealed the absence of unmyelinated fibers. The small myelinated fibers may also be slightly reduced in Classification
REFERENCES ' Kriel RL. Abnormalities of sensory perception. In: The practice of pediatric neurology. Edited by Swaiman KF and Wright FS. The CV Mosby Co, Saint Louis 1975, pp 161-167.
TABLE 1 with impaired pain Perception touch temper
perception'"'''
.10
Sweating
Tendon Reflexes
Axon Reflexes
Dislribniion of Sensory Loss
Motor Deficit
Onset 10-30 years
Intelligence
pain
Normal
No
±
No
Normal
decreased
No
acral
No
birth
Normal
No
No
No
Normal
decreased
No
acral
No
autosomal recessive
birth
Normal or decreased
No
Yes reduced increased decreased
No
universal
No
autosomal recessive
birth
decreased
No
Yes
No
universal hypotonia
Syndrome
Hereditary
Congenital sensory neuropathy, type-I Congenital sensory neuropathy, type-II Familial dysautonomia (Congenital sensory neuropathy, type-II)
autosomal dominant autosomai recessive
Congenital sensory neuropathy with anhidrosis type-IV
of syndromes
number. This was observed only in type-IV sensory neuropathy.' The absence of pain and thermal sensation is responsible for the burns, wounds, self-mutilation of the tongue and painless bone fractures. Anhidrosis is responsible for the febrile episodes. CSNA patients can present hypotrichosis of the scalp, but the eyebrows, nails and teeth are normal.'" Our patient presented at pre-school age with significant dental problems. In this syndrome, the sweat glands do not respond to injection of pilocarpine, neostigmine, mecholyl, acetycholine or adrenaline'*" but only to simultaneous injection of acetylcholine with adrenaline.' After iontophoresis with pilocarpine Lee et aP were able to collect a small amount of sweat. In our sweat gland tests we observed that the intradermal injection of prostigmine did not produce sweating (as expected), because the anhidrosis disturbance is due to the absence of nerves.'^ Intradermal injection of metacholine and iontophoresis with acetylcholine produced a poor response. This difference from the literature was possibly due to the more sensitive method which we used (starchiodine-plastic impression method) which permitted us to study the sweat production in each individual gland. During the "sweat gland training" t e s f the results were also positive but poor. This can be explained by the fact that the sweat glands are non innervated'^ although anatomically normal.'"^
106
No
absent
decreased
CONGENITAL SENSORY NEUROPATHY WITH ANHIDROSIS Hatzis J, Varelzidis A, Tosca A, Stratigos J, Sweat gland disturbances in granuloma annulare and necrobiosis lipoidica. Br J Dermatol 1983, 108: 705-709. Rothman S. Physiology and Biochemistry of the Skin. Chicago, University of Chicago Press, 1954. Verity CM, Dunn HG, Berry K. Children with reduced sensitivity to pain: Assessment of hereditary sensory neuropathy types II and IV. Develop Med Child Neurol 1982, 24: 185-197. Collins KJ, Grockford GW, Weiner JS. The role of glandular activity in the increased sweat response of heat acclimatization. J Physiot 1963, 169: 12-13. Hatzis J, Tosca A, Moulopoulou-Karakitsou K, Stratigos J, Varelzidis A, Capetanakis J. Anhidrotic ectodermal dysplasia. Therapeutic attempts. Dermatologica 1982, 164: 54-61. Vassella F, Emrich HM, Kraus-Ruppert R et al. Congenital sensory neuropathy with anhidrosis. Arch Dis Child 1968, 43: 124-130.
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Lee EL, Oh GC, Lam KL, Parameswaran N. Congenital sensory neuropathy with anhidrosis: a case report. Pediatrics 1976, 57: 259-262, Goebel HH, Veit S, Dyck PJ. Confirmation of virtual unmyelinated fiber absence in hereditary sensory neuropathy type IV. J Neuropathol Exp Neurol 1980, 39: 670-675. Axelrod FB, Pearson J. Congenital sensory neuropathies. Diagnostic distinction from familial dysautonomia. AJDC 1984, 138: 947-954. Ishii N, Kawaguchi H, Miyakawa K, Nakajima H. Congenital sensory neuropathy with anhidrosis. Arch Dermatol 1988, 124: 564-566. Langer J, Geobel HH, Veit S. Eccrine sweat glands are not innervated in hereditary sensory neuropathy type IV. Acta Neuropathol 1981, 54: 199-202.