British Journal of Dermatology (1990) 122, 689-697.
KeratitiSj ichthyosis and deafness (KID)-syndrome: report of three cases and a review of the literature K.LANGER, K.KONRAD AND K.WOLFF Department of Dermatology I, University of Vienna Medical School, Vienna, Austria Accepted for publication 6 November 1989
SUMMARY
We report three patients with keratitis, ichthyosis and deafness (KID)-syndroine. All had characteristic hyperkeratotic skin lesions and neurosensory hearing defects. Two had ophthalmologic symptoms. The third patient did not have eye involvement at the age of 3 years, but exhibited the other typical signs of the syndrome. In none of the three cases were any of the patients' relatives affected, and a spontaneous new mutation is the most likely explanation for the occurrence of this rare syndrome. Histopathological and electron microscopic studies revealed orthohyperkeratosis but no other pathology and no abnormal deposits of glycogen were found. Treatment with the aromatic retinoid etretinate proved to be of little value in any of the patients. The necessity for early audiologic and ophthalmologic evaluation and the need for lifelong medical care for patients with KID-syndrome is emphasized.
A distinct genodermatosis, the association of hyperkeratotic skin lesions, a neurosensory hearing defect, and a vascularizing keratitis occurring in early infancy or childhood, has been termed the keratitis, ichthyosis and deafness (KID)-syndrome by Skinner et al.^ The earliest publication of a patient with features of this syndrome dates back to 1915.^ Here, three patients with KID-syndrome are described, who have been seen in the Departments of Dermatology of Vienna and Innsbruck, Austria. CASE REPORTS Case I
N.M., male aged 8. The boy was born after an uncomplicated pregnancy. The family history was unrevealing, and his sister was normal. Consanguinity was not reported. At birth, his skin was red all over but without scaling. Within the first 5 months, brown-black scaly lesions with deep furrows appeared over the elbows, extensor aspects of tbe knees and the dorsa of the hands. Tbe skin of the face was red with fine telangiectases and appeared thickened (Fig. i). The skin Correspondence: Professor K.Wolff, Department of Dermatology I, University of Vienna Medical School, Alser Strasse 4, A-1090 Vienna, Austria.
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FIGURE I. Case i,boy, Syearsold. Scarring alo[>ecia, brownish-red hyperkeraratic lesions on the earlobes and the cheeks; multiple teleangiectases. Note hearing aid.
texture was generally velvety, but in areas was rough and sandpaper-like. On both ears and cheeks greyish-brown hyperkeratotic verrucous plaques were seen. Tiny horny spikes were seen in a foUicular arrangement all over the body (Fig. 2). The palms and soles were hyperkeratotic and since the papillary skin lines were both prominent and interrupted, the surface of the skin had a reticulate appearance. There was scarring alopecia on the occiput (due to recurrent
FIGURE 2. Case I. Tiny homy spikes on the extensor aspects of the fingers.
KID syndrome pyoderma) atid on the remainder of the scalp the hair was sparse, short and fluffy and of the veilous type. White and red blood cell counts, blood chemistry and protein electrophoresis showed no abnormalities. Serum IgE level was elevated (650 kU/1, normal 100 kU/I). Lymphocyte stimulation tests with concanavalin A and phytohaemagglutinin were normal. The excretion pattern of amino acids in the urine was normal; phytanic acid could not be detected in the serum. X-rays of the chest, skull, nasal sinuses, the spinal column and hands showed no abnormalities. Ophthalmologic examination revealed conjunctivitis; the corneas, lenses and fundi were normal as was his visual acuity. A bilateral neurosensory hearing defect had been diagnosed at the age of 4, and the boy had bilateral hearing aids. His mental development was normal. Treatment with etretinate was started at a dose of i mg/kg body weight per day with topical emollients added. After 4 months of etretinate therapy there were no side-effects except for dryness of the lips, but there was no beneficial effect and treatment was switched to 13-C15 retinoic acid (Roaccutane*), at a dose of i mg/kg body weight per day. Severe headaches developed and therapy was changed back to etretinate and moderate improvement was noted, but the treatment had to be stopped again because of an elevation of the serum bilirubin level. A severe relapse occurred within 3 weeks. After this, the patient was lost to follow-up. Case 2 H.K., female aged 3. The girl was born after an uncomplicated pregnancy. The family history was unremarkable and there was no consanguinity. The patient's 5-year-old sister was normal. The patient's skin at birth was reported to have had a peculiar bluish-white colour and shortly after birth she developed hyperkeratotic lesions. The finger- and toe-nails were absent at birth, but developed during the first 3 years of life, and the toe-nails became dystrophic. At the time of examination, sharply demarcated brownish-red plaques with a velvety surface were present
FIGURE 3. Case 2, girl, 3 years old. Brownish, rippled leather-like plaques over the knees.
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around the mouth, on the cheeks, the tip of the nose, the chin and the ear lobes. Brownish-grey, hyperkeratotic leather-like plaques with a rippled surface were seen over the knees, the buttocks and the dorsa of the feet (Fig. 3). Her ability to sweat decreased but heat intolerance was not reported. The child had sparse, silvery-white, almost unmanageable scalp hair, but the hair shafts showed no abnormalities. Eyebrows and eyelashes were completely absent. The palms and soles appeared as in case i. White and red blood cell counts, blood chemistry, scrum IgE levels, serum immunoglobulin levels, and lymphocyte stimulation tests were within normal limits. Tone-audiograms and a brain stem audiometry revealed a moderate-degree bilateral, neurosensory hearing defect localized in the cochlea and also a dysfunction of the acoustic nerve. There was a delay in speech development for which therapy was initiated. Ophthalmological examination was normal as was her growth and mental development. Treatment with emollients and keratolytic agents (10",, urea) did not lead to any noticeable improvement. Etretinate (Tigason*) therapy was initiated at a dose of 0 8 mg/kg body weight on alternate days, and later daily. She has received etretinate elsewhere over a period of 8 months, but without much improvement and this therapy has now been discontinued. Case 3 G.K., female aged 21. The girl was bom after an uneventful pregnancy with normal appearing skin. The family history was unremarkable without any consanguinity. At the age of 6 weeks moist lesions developed on both earlobes and spread over the whole body, but eventually a universal dryness of the skin developed. In the first 2 years of life, the child suffered from multiple recurrent pyodermas. At the age of 6, tinea capitis led to a scarring alopecia and
FIGURE 4. Case 3, female, 21 years old. Typical appearance of the face with lichenification of the skin, furrows around the mouth, sparse temporal hair. Numerous milia in the periorbiial region.
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FIGURE 5. Case 3. Peculiar pattern of dcnnatoglyphics, typical of KID-syndrome patients.
recurrent episodes of conjunctivitis were reported. The whole skin showed diffuse, fine, scaly hyperkeratosis. On the trunk she was anhidrotic, but she sweated normally in the axillae. On examination there wereflaterythematous, hyperkeratotic lesions with a velvety to spiny surface appearing symmetrically on both cheeks (Fig. 4). Over the elbows and knees the skin was thickened, greyish, partly red and rippled. The palms and soles appeared as described for case I (Fig. 5). The scalp hair was sparse, partly as a result of cicatricial alopecia; the pubic and axillary hair were absent, but no evidence of scarring or atrophy was noticed in these regions. The toenails were dystrophic and the right mammary gland was hypoplastic. Ophthalmological examination revealed stippled opacities of the corneas, but visual acuity was normal. A high-grade bilateral neurosensory hearing defect had been diagnosed at the preschool age and the patient used a hearing aid. Her intellectual development was normal. White and red blood counts and protein electrophoresis showed normal results. Antinuclear antibodies and autoantibodies against smooth muscle cells, thyroglobulin, thyroid microsomes and gastric parietal cells were not detected. The T-helper/T-suppressor cell ratio was normal. The serum igE was elevated (980 kU/1; normal range, 100 kU/1). A trial of PUVA-therapy was discontinued after 3 weeks because of uncontrollable photosensitivity reactions even at low doses of UVA. Retinoid therapy with etretinate at a dose of I mg/kg body weight in conjunction with topical emollients led to some improvement but this had to be stopped after 4 years because of intractable pruritus and hair loss. Hisiopathology Skin biopsy specimens from the three patients were taken from various sites (case i, left knee; case 2, buttock; case 3, left lower leg and left palm) and showed similar features. The epidermis
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FIGURE 6. Massive hyperkeratosis, hypergnmulosis and acanthosis. Sparse lymphohisiiocytic infiltrate in the upper deraiis (Case 3, left lower leg, hacmaioxylin and eosin stain, x 200).
was acanthotic with an irregular, spiked surface, hypergranulosis and massive orthohyperkeratosis. The foUicular openings were dilated and filled with horny material. The intraepidermal sweat gland ducts were dilated, but otherwise normal. A sparse lymphohistiocytic infiltrate was found in the upper dermis (Fig. 6). The eccrine sweat glands and dermal nerves appeared normal and the PAS-stain did not reveal any abnormal deposits of glycogen. In the specimen from the palm, intraepidermal sweat-gland ducts were found predominantly in the 'valleys' between the horny spikes, where the stratum corneum cells appeared less tightly packed, and therefore less coherent. A second biopsy in case i after 10 months of etretinate treatment showed no significant changes. Electron microscopy
Ultrastructural studies of all three patients showed similar features. The epidermis was acanthotic and normally stratified and the stratum corneum was composed of tightly packed layers of comified cells. The keratinocytes of the basal and lower spinous layers had abundant cytoplasm with an increased number of organelles. The keratin filament bundles appeared thickened and clumped, and their insertion into desmosomes appeared accentuated (Fig. 7). The membrane coating granules appeared normal and were present in normal numbers. In the stratum granulosum, the keratohyalin granules and inserting keratin filament bundles surrounded the nuclei in a shell-like fashion. Some of the nuclei of the keratinocytes in the upper layers of the epidermis were deeply indented. Melanocytes, Langerhans cells, the dermal appendages, blood vessels and nerves showed no abnormalities. No abnormal deposits of glycogen or any other material were found. DISCUSSION
Ichthyosiform skin disorders constitute a large group of genodermatoses which can be classified by their mode of inheritance, clinical appearance, histopathology and associated symptoms.^ In some, distinctive biochemical defects have been described.** Congenital deafness, disorders of hair, nails and teeth and mental retardation are found in a variety of mostly rare syndromes.*
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FIGURE 7. Electron micrograph; stratum spinosum. Keratinocytes wiih abundant cyioplasm, increased numbers of mitochondria (M) and prominent bundles of tonofilaments (T). N, nucleus (Case i, left knee.
The eombination of an ichthyosiform dermatosis with deafness and keratitis reported here was first described in 1915^ and similar cases were reported under various names.^""' In 1981 Skinner et al} proposed the name keratitis, ichthyosis and deafness (KID)-syndrome for this disorder. There are a number of clinical criteria for the diagnosis of KID-syndrome. A striking characteristic of patients with KID-syndrome is their close likeness. Children with KIDsyndrome look prematurely aged. The skin of the face is dry, with a greyish-brown tone. On the cheeks, the chin and the earlobes are found sharply demarcated, usually erythematous hyperkeratotic plaques. A prominent fold of the lower eyelids is occasionally seen. Hyperkeratotic plaques are typically found over the elbows, knees, dorsa of hands and feet. A fine lamellar hyperkeratosis and tiny horny spikes occur all over the body, and a hyperkeratosis of the palms and soles with a leather-like appearance, tiny pits, spikes and interrupted creases are also characteristic. Other typical signs of KID-syndrome are the sparse and unmanageable scalp hair, the sparse and often absent eyebrows, eyelashes, axillary and pubic hair and often hyperkeratotic and dystrophic nails. In two of our patients only the toe-nails were dystrophic, whereas thefinger-nailswere normal. The teeth are normally developed in some patients, but in others they have been described as small and malformed, and are likely to develop caries.'-'^"'^ Recurrent skin infections are a major problem in patients with KID-syndrome.'°''^**^'''' Pyodermas, fungal infections often leading to scarring alopecia and recurrent scabies'^ have
696 K.Langer et al. been reported. A large variety of pathogenic bacteria have been isolated from the skin of patients with this syndrome' •' ^-''' but apart from a defect of neutrophil chemotaxis observed in a patient with probable KID-syndrome** the propensity of these patients to develop infections remains unexplained. The definition of the syndrome comprises keratitis and deafness in addition to the ichthyotic skin lesions. Neurosensory deafness is usually present at birth but is often only noted later on in life because speech development is delayed.^'^""*''''"''*''^'^* Each of our patients had a neurosensory hearing defect. A vascularizing keratitis preceeded by a purulent blepharoconjunctivitis, and leading to comeal ulcerations and pannus formation eventually resulting in blindness, is found in most patients with KID-syndrome. Two of our patients (cases i and 3) had recurrent inflammations of the conjunctivae. In one case (3), stippled opacities of the corneae were also found, but these did not impair visual acuity. As the development of eye disorders has been reported to occur as late as theageof 11/•**'"• "•'^•'*'-^'' these may still develop inour 3-year-old patient, who at the time of examination had no ocular problems. Only a few of the KID-syndrome patients described in the literature were mentally retarded;^''^^ in our patients intellectual development was normal. A unilateral hypoplasia of the mammary gland, which was found in one of our patients (case 3) has occurred in another case.^ A peripheral neuropathy was not detected in our patients. Histopathological studies in our patients showed no abnormal amounts of keratin in the sweat-gland ducts. The appendages were normal and contained no abnormal deposits of glycogen as reported in one patient.^"^ Electron microscopy showed a normally stratified epidermis with a thick lamellar hyperkeratosis in all three cases, keratin filament bundles were thickened and clumped and the keratohyalin granules were distributed in a shell-like fashion around the nucleus. Peculiarly shaped nuclei with deep indentations were found in all patients, but the significance of this remains unclear. In cultured keratinocytes from a patient with a condition resembling KID-syndrome, no abnormalities of keratinization were found, and immunofiuorescence studies of skin biopsies using monoclonal antibodies against prekeratin, filaggrin and involucrin have revealed normal staining patterns.^^^ None of our patients had relatives with skin disorders, hearing impairment or ophthalmologic problems and there was no consanguinity. KID-syndrome occurs mostly as a single case and in both sexes, and may therefore be considered as a result of spontaneous new mutation. However, one example of a vertical transmission of KID-syndrome from father to daughter has recently been reported.' ^ An eventually fatal squamous cell carcinoma of the skin developed in a member of this family (father), and squamous cell carcinomas of the skin and the tongue as well as other malignant tumours have been reported in other patients.^'•^^•^•* Treatment of patients with KID-syndrome is difficult and only symptomatic relief can be achieved by keratolytic agents and therapy for skin infections. Retinoids have been reported to be beneficial in hyperkeratotic, ichthyotic disorders,^^•^*^ but as in our cases, seem to be at most of only moderate value for the treatment of KID-syndrome. KID-syndrome is a rare disorder. Its early diagnosis is important, and the early wearing of hearing aids and starting of speech therapy can prevent the impairment of speech development. Life-long ophthalmologic examinations are necessary to avoid corneal damage. The prognosis seems to be good in general, but no long-term studies of the outcome of KID-syndrome patients exist. The occurrence of malignant tumours in some patients with KID-syndrome suggests that the genetic defect enhances the chance for the development of malignancy, and also emphasizes the need for periodical examination of the affected individuals.
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ACKNOWLEDGMENTS
The authors wish to thank Peter Fritsch, M.D. (Chairman, Department of Dermatology, University of Innsbruck) for permission to include case 3 in this study and Ema Jaschke, M.D. Kufstein (Austria) for providing care for this patient; Wilfried Kohler, M.D., Department of Otolaryngology II, University of Vienna, for performing audiologic tests in case 2, Mrs Uschi Hornick and Mr Heinz Gaudek for technical assistance, and Mrs Sylvia Hermanek for typing tbe manuscript. REFERENCES 1 Skinner BA, Greist MC, Norim AL. The keratitis, ichthyosis, and deafness (KID) syndrome. Arch Dermatol 1981; 117:285-9. 2 Bums FS. A case of generalized congenital keratodenna with unusual involvement of the eyes and nasal and buccal mucous membranes. J' Cuian Dis 1915; 33: 255-60. 3 Wells RS, Kerr CB. Genetic classification of ichthyosis. Arch Dermatol 1965; 92: r-6. 4 Baden HP. Ichthyosiform Dermatoses. In: Dermaiology in General Medicine (Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds), 3rd edn. McGraw Hill, 1987; 1017-25. 5 Voigtiander V. Hereditare Verhomungsstorungen und Taubheit. Z Hautkr 1977; 52: 1017-25. 6 Taussig LR. Ichthyosis with involvement of the cornea. Arch Dermatol 1939; 40: 504-5. 7 Morris J, Ackerman AB, Koblenzer PJ. Generalized spiny hyperkeratosis, universal alopecia and deafness. Arch Dermaiol 1969; 100: 692-8. 8 Beare JM, Nevin NC, Froggatt P ef al. Atypical erythrokeratoderma with deafness, physical retardation and peripheral neuropathy. Br J Dermatol 1972; 87: 308-14. 9 Wilson FM, Grayson M, Pieroni D. Comeal changes in ectodermal dysplasia. Am J Ophthalmol 1973; 75: 17-25. 10 Rycroft RJG, Moynahan EJ, Wells RS. Atypical ichthyosiform erythroderma, deafness and keratitis. Br J Dermatol t976;94: 211-17. 11 Cremers CWRJ, Philipsen VMJG, Mali JWH. Deafness, ichthyosiform erythroderma, comeal involvement, photophobia and dental dysplasia, J Laryngol Owl 1977; 91: 585-7. 12 BrittonHjLustigJ,Thompson BJ era/. Keratosisfollicularisspinulosadecalvans. Arch Dermatol 1978; 114:761-4. 13 Silvestri DL. Ichthyosiform dermatosis and deafness. Arch Dermaiol 1978; 114: 1243-4. 14 Senrcr ThP, Jones KL, Sakati N, Nyhan WL. Atypical ichthyosiform erythroderma and congenital neurosensory deafness—a distinct syndrome. J Pediarr 1978; 92: 68-72. 15 Cram DL, Resneck JS, Jackson WB. A congenital ichthyosifonn syndrome with deafness and keratitis. Arch Dermaiol 1979; 115: 467-71. 16 Van Everdingen JJE, Rampen FHJ, van der Schaar WW. Normal sweating and tear production in congenital ichthyosiform erythrodenna with deafness and keratitis. Acta Dermatovener 1981; 62: 76-7. 17 Grob JJ, Breton A, Bonafe JL et al. Keratitis, ichthyosis and deafness (KID) syndrome. Vertical transmission and death from multiple squamous cell carcinomas. Arch Dermatol 1987; 123: 777-82. 18 Pincus StH, Thomas IT, Clark RA et al. Defective neutrophil chemotaxis with variant ichthyosis, hyperimmunoglobuiinemia E, and recurrent infections. J Pediatr 1975; 87: 908-11. 19 Baden HP, Alper JC. Ichthyosiform dermatosis, keratitis and deafness. Arch Dermatol 1977; 113: 1701-4. 20 Jurecka W, Aberer E, Mainitz M et al. Keratitis, ichthyosis, and deafness syndrome with glycogen storage. Arch Dermatol 1985; 121: 799-801. 21 Lancaster L, Jr, Fournet LF. Carcinomaof the tongue in a child: report ofa case. J'Ora^AfajoV/d/acSwty 1969; 17: 269-70. 22 Carey AB, Burke WA, Park HK. Malignant fibrous histiocytoma in keratitis, ichthyosis, and deafness syndrome. J Am Acad Dermaiol igSS; 19: 1124-6. 23 Baden HP, Bronstein BR. Ichthyosiform dermatosis and deafness. Report of a case and review of the literature. Arch Dermatol 1988; 124: 102-6. 24 Madriaga J, Fromowitz F, Phillips M et al. Squamous cell carcinoma in congenital ichthyosis with deaihess and keratitis. A case report and review of the literature. Cancer t9S6; 57: 2026-9. 25 Eriksen L, Cormane RH. Oral retinoic acid as therapy for congenital ichthyosiform erythroderma. BrJ Dermatol 1975; 92: 343-526 Peck GL, DiGiovanna JJ. Retinoids. In: Dermatology in General Medicine (Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, edsj, 3rd edn. McGraw Hill, 2583-609.
KeratitiSj ichthyosis and deafness (KID)-syndrome: report of three cases and a review of the literature K.LANGER, K.KONRAD AND K.WOLFF Department of Dermatology I, University of Vienna Medical School, Vienna, Austria Accepted for publication 6 November 1989
SUMMARY
We report three patients with keratitis, ichthyosis and deafness (KID)-syndroine. All had characteristic hyperkeratotic skin lesions and neurosensory hearing defects. Two had ophthalmologic symptoms. The third patient did not have eye involvement at the age of 3 years, but exhibited the other typical signs of the syndrome. In none of the three cases were any of the patients' relatives affected, and a spontaneous new mutation is the most likely explanation for the occurrence of this rare syndrome. Histopathological and electron microscopic studies revealed orthohyperkeratosis but no other pathology and no abnormal deposits of glycogen were found. Treatment with the aromatic retinoid etretinate proved to be of little value in any of the patients. The necessity for early audiologic and ophthalmologic evaluation and the need for lifelong medical care for patients with KID-syndrome is emphasized.
A distinct genodermatosis, the association of hyperkeratotic skin lesions, a neurosensory hearing defect, and a vascularizing keratitis occurring in early infancy or childhood, has been termed the keratitis, ichthyosis and deafness (KID)-syndrome by Skinner et al.^ The earliest publication of a patient with features of this syndrome dates back to 1915.^ Here, three patients with KID-syndrome are described, who have been seen in the Departments of Dermatology of Vienna and Innsbruck, Austria. CASE REPORTS Case I
N.M., male aged 8. The boy was born after an uncomplicated pregnancy. The family history was unrevealing, and his sister was normal. Consanguinity was not reported. At birth, his skin was red all over but without scaling. Within the first 5 months, brown-black scaly lesions with deep furrows appeared over the elbows, extensor aspects of tbe knees and the dorsa of the hands. Tbe skin of the face was red with fine telangiectases and appeared thickened (Fig. i). The skin Correspondence: Professor K.Wolff, Department of Dermatology I, University of Vienna Medical School, Alser Strasse 4, A-1090 Vienna, Austria.
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FIGURE I. Case i,boy, Syearsold. Scarring alo[>ecia, brownish-red hyperkeraratic lesions on the earlobes and the cheeks; multiple teleangiectases. Note hearing aid.
texture was generally velvety, but in areas was rough and sandpaper-like. On both ears and cheeks greyish-brown hyperkeratotic verrucous plaques were seen. Tiny horny spikes were seen in a foUicular arrangement all over the body (Fig. 2). The palms and soles were hyperkeratotic and since the papillary skin lines were both prominent and interrupted, the surface of the skin had a reticulate appearance. There was scarring alopecia on the occiput (due to recurrent
FIGURE 2. Case I. Tiny homy spikes on the extensor aspects of the fingers.
KID syndrome pyoderma) atid on the remainder of the scalp the hair was sparse, short and fluffy and of the veilous type. White and red blood cell counts, blood chemistry and protein electrophoresis showed no abnormalities. Serum IgE level was elevated (650 kU/1, normal 100 kU/I). Lymphocyte stimulation tests with concanavalin A and phytohaemagglutinin were normal. The excretion pattern of amino acids in the urine was normal; phytanic acid could not be detected in the serum. X-rays of the chest, skull, nasal sinuses, the spinal column and hands showed no abnormalities. Ophthalmologic examination revealed conjunctivitis; the corneas, lenses and fundi were normal as was his visual acuity. A bilateral neurosensory hearing defect had been diagnosed at the age of 4, and the boy had bilateral hearing aids. His mental development was normal. Treatment with etretinate was started at a dose of i mg/kg body weight per day with topical emollients added. After 4 months of etretinate therapy there were no side-effects except for dryness of the lips, but there was no beneficial effect and treatment was switched to 13-C15 retinoic acid (Roaccutane*), at a dose of i mg/kg body weight per day. Severe headaches developed and therapy was changed back to etretinate and moderate improvement was noted, but the treatment had to be stopped again because of an elevation of the serum bilirubin level. A severe relapse occurred within 3 weeks. After this, the patient was lost to follow-up. Case 2 H.K., female aged 3. The girl was born after an uncomplicated pregnancy. The family history was unremarkable and there was no consanguinity. The patient's 5-year-old sister was normal. The patient's skin at birth was reported to have had a peculiar bluish-white colour and shortly after birth she developed hyperkeratotic lesions. The finger- and toe-nails were absent at birth, but developed during the first 3 years of life, and the toe-nails became dystrophic. At the time of examination, sharply demarcated brownish-red plaques with a velvety surface were present
FIGURE 3. Case 2, girl, 3 years old. Brownish, rippled leather-like plaques over the knees.
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around the mouth, on the cheeks, the tip of the nose, the chin and the ear lobes. Brownish-grey, hyperkeratotic leather-like plaques with a rippled surface were seen over the knees, the buttocks and the dorsa of the feet (Fig. 3). Her ability to sweat decreased but heat intolerance was not reported. The child had sparse, silvery-white, almost unmanageable scalp hair, but the hair shafts showed no abnormalities. Eyebrows and eyelashes were completely absent. The palms and soles appeared as in case i. White and red blood cell counts, blood chemistry, scrum IgE levels, serum immunoglobulin levels, and lymphocyte stimulation tests were within normal limits. Tone-audiograms and a brain stem audiometry revealed a moderate-degree bilateral, neurosensory hearing defect localized in the cochlea and also a dysfunction of the acoustic nerve. There was a delay in speech development for which therapy was initiated. Ophthalmological examination was normal as was her growth and mental development. Treatment with emollients and keratolytic agents (10",, urea) did not lead to any noticeable improvement. Etretinate (Tigason*) therapy was initiated at a dose of 0 8 mg/kg body weight on alternate days, and later daily. She has received etretinate elsewhere over a period of 8 months, but without much improvement and this therapy has now been discontinued. Case 3 G.K., female aged 21. The girl was bom after an uneventful pregnancy with normal appearing skin. The family history was unremarkable without any consanguinity. At the age of 6 weeks moist lesions developed on both earlobes and spread over the whole body, but eventually a universal dryness of the skin developed. In the first 2 years of life, the child suffered from multiple recurrent pyodermas. At the age of 6, tinea capitis led to a scarring alopecia and
FIGURE 4. Case 3, female, 21 years old. Typical appearance of the face with lichenification of the skin, furrows around the mouth, sparse temporal hair. Numerous milia in the periorbiial region.
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FIGURE 5. Case 3. Peculiar pattern of dcnnatoglyphics, typical of KID-syndrome patients.
recurrent episodes of conjunctivitis were reported. The whole skin showed diffuse, fine, scaly hyperkeratosis. On the trunk she was anhidrotic, but she sweated normally in the axillae. On examination there wereflaterythematous, hyperkeratotic lesions with a velvety to spiny surface appearing symmetrically on both cheeks (Fig. 4). Over the elbows and knees the skin was thickened, greyish, partly red and rippled. The palms and soles appeared as described for case I (Fig. 5). The scalp hair was sparse, partly as a result of cicatricial alopecia; the pubic and axillary hair were absent, but no evidence of scarring or atrophy was noticed in these regions. The toenails were dystrophic and the right mammary gland was hypoplastic. Ophthalmological examination revealed stippled opacities of the corneas, but visual acuity was normal. A high-grade bilateral neurosensory hearing defect had been diagnosed at the preschool age and the patient used a hearing aid. Her intellectual development was normal. White and red blood counts and protein electrophoresis showed normal results. Antinuclear antibodies and autoantibodies against smooth muscle cells, thyroglobulin, thyroid microsomes and gastric parietal cells were not detected. The T-helper/T-suppressor cell ratio was normal. The serum igE was elevated (980 kU/1; normal range, 100 kU/1). A trial of PUVA-therapy was discontinued after 3 weeks because of uncontrollable photosensitivity reactions even at low doses of UVA. Retinoid therapy with etretinate at a dose of I mg/kg body weight in conjunction with topical emollients led to some improvement but this had to be stopped after 4 years because of intractable pruritus and hair loss. Hisiopathology Skin biopsy specimens from the three patients were taken from various sites (case i, left knee; case 2, buttock; case 3, left lower leg and left palm) and showed similar features. The epidermis
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FIGURE 6. Massive hyperkeratosis, hypergnmulosis and acanthosis. Sparse lymphohisiiocytic infiltrate in the upper deraiis (Case 3, left lower leg, hacmaioxylin and eosin stain, x 200).
was acanthotic with an irregular, spiked surface, hypergranulosis and massive orthohyperkeratosis. The foUicular openings were dilated and filled with horny material. The intraepidermal sweat gland ducts were dilated, but otherwise normal. A sparse lymphohistiocytic infiltrate was found in the upper dermis (Fig. 6). The eccrine sweat glands and dermal nerves appeared normal and the PAS-stain did not reveal any abnormal deposits of glycogen. In the specimen from the palm, intraepidermal sweat-gland ducts were found predominantly in the 'valleys' between the horny spikes, where the stratum corneum cells appeared less tightly packed, and therefore less coherent. A second biopsy in case i after 10 months of etretinate treatment showed no significant changes. Electron microscopy
Ultrastructural studies of all three patients showed similar features. The epidermis was acanthotic and normally stratified and the stratum corneum was composed of tightly packed layers of comified cells. The keratinocytes of the basal and lower spinous layers had abundant cytoplasm with an increased number of organelles. The keratin filament bundles appeared thickened and clumped, and their insertion into desmosomes appeared accentuated (Fig. 7). The membrane coating granules appeared normal and were present in normal numbers. In the stratum granulosum, the keratohyalin granules and inserting keratin filament bundles surrounded the nuclei in a shell-like fashion. Some of the nuclei of the keratinocytes in the upper layers of the epidermis were deeply indented. Melanocytes, Langerhans cells, the dermal appendages, blood vessels and nerves showed no abnormalities. No abnormal deposits of glycogen or any other material were found. DISCUSSION
Ichthyosiform skin disorders constitute a large group of genodermatoses which can be classified by their mode of inheritance, clinical appearance, histopathology and associated symptoms.^ In some, distinctive biochemical defects have been described.** Congenital deafness, disorders of hair, nails and teeth and mental retardation are found in a variety of mostly rare syndromes.*
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FIGURE 7. Electron micrograph; stratum spinosum. Keratinocytes wiih abundant cyioplasm, increased numbers of mitochondria (M) and prominent bundles of tonofilaments (T). N, nucleus (Case i, left knee.
The eombination of an ichthyosiform dermatosis with deafness and keratitis reported here was first described in 1915^ and similar cases were reported under various names.^""' In 1981 Skinner et al} proposed the name keratitis, ichthyosis and deafness (KID)-syndrome for this disorder. There are a number of clinical criteria for the diagnosis of KID-syndrome. A striking characteristic of patients with KID-syndrome is their close likeness. Children with KIDsyndrome look prematurely aged. The skin of the face is dry, with a greyish-brown tone. On the cheeks, the chin and the earlobes are found sharply demarcated, usually erythematous hyperkeratotic plaques. A prominent fold of the lower eyelids is occasionally seen. Hyperkeratotic plaques are typically found over the elbows, knees, dorsa of hands and feet. A fine lamellar hyperkeratosis and tiny horny spikes occur all over the body, and a hyperkeratosis of the palms and soles with a leather-like appearance, tiny pits, spikes and interrupted creases are also characteristic. Other typical signs of KID-syndrome are the sparse and unmanageable scalp hair, the sparse and often absent eyebrows, eyelashes, axillary and pubic hair and often hyperkeratotic and dystrophic nails. In two of our patients only the toe-nails were dystrophic, whereas thefinger-nailswere normal. The teeth are normally developed in some patients, but in others they have been described as small and malformed, and are likely to develop caries.'-'^"'^ Recurrent skin infections are a major problem in patients with KID-syndrome.'°''^**^'''' Pyodermas, fungal infections often leading to scarring alopecia and recurrent scabies'^ have
696 K.Langer et al. been reported. A large variety of pathogenic bacteria have been isolated from the skin of patients with this syndrome' •' ^-''' but apart from a defect of neutrophil chemotaxis observed in a patient with probable KID-syndrome** the propensity of these patients to develop infections remains unexplained. The definition of the syndrome comprises keratitis and deafness in addition to the ichthyotic skin lesions. Neurosensory deafness is usually present at birth but is often only noted later on in life because speech development is delayed.^'^""*''''"''*''^'^* Each of our patients had a neurosensory hearing defect. A vascularizing keratitis preceeded by a purulent blepharoconjunctivitis, and leading to comeal ulcerations and pannus formation eventually resulting in blindness, is found in most patients with KID-syndrome. Two of our patients (cases i and 3) had recurrent inflammations of the conjunctivae. In one case (3), stippled opacities of the corneae were also found, but these did not impair visual acuity. As the development of eye disorders has been reported to occur as late as theageof 11/•**'"• "•'^•'*'-^'' these may still develop inour 3-year-old patient, who at the time of examination had no ocular problems. Only a few of the KID-syndrome patients described in the literature were mentally retarded;^''^^ in our patients intellectual development was normal. A unilateral hypoplasia of the mammary gland, which was found in one of our patients (case 3) has occurred in another case.^ A peripheral neuropathy was not detected in our patients. Histopathological studies in our patients showed no abnormal amounts of keratin in the sweat-gland ducts. The appendages were normal and contained no abnormal deposits of glycogen as reported in one patient.^"^ Electron microscopy showed a normally stratified epidermis with a thick lamellar hyperkeratosis in all three cases, keratin filament bundles were thickened and clumped and the keratohyalin granules were distributed in a shell-like fashion around the nucleus. Peculiarly shaped nuclei with deep indentations were found in all patients, but the significance of this remains unclear. In cultured keratinocytes from a patient with a condition resembling KID-syndrome, no abnormalities of keratinization were found, and immunofiuorescence studies of skin biopsies using monoclonal antibodies against prekeratin, filaggrin and involucrin have revealed normal staining patterns.^^^ None of our patients had relatives with skin disorders, hearing impairment or ophthalmologic problems and there was no consanguinity. KID-syndrome occurs mostly as a single case and in both sexes, and may therefore be considered as a result of spontaneous new mutation. However, one example of a vertical transmission of KID-syndrome from father to daughter has recently been reported.' ^ An eventually fatal squamous cell carcinoma of the skin developed in a member of this family (father), and squamous cell carcinomas of the skin and the tongue as well as other malignant tumours have been reported in other patients.^'•^^•^•* Treatment of patients with KID-syndrome is difficult and only symptomatic relief can be achieved by keratolytic agents and therapy for skin infections. Retinoids have been reported to be beneficial in hyperkeratotic, ichthyotic disorders,^^•^*^ but as in our cases, seem to be at most of only moderate value for the treatment of KID-syndrome. KID-syndrome is a rare disorder. Its early diagnosis is important, and the early wearing of hearing aids and starting of speech therapy can prevent the impairment of speech development. Life-long ophthalmologic examinations are necessary to avoid corneal damage. The prognosis seems to be good in general, but no long-term studies of the outcome of KID-syndrome patients exist. The occurrence of malignant tumours in some patients with KID-syndrome suggests that the genetic defect enhances the chance for the development of malignancy, and also emphasizes the need for periodical examination of the affected individuals.
KID syndrome
697
ACKNOWLEDGMENTS
The authors wish to thank Peter Fritsch, M.D. (Chairman, Department of Dermatology, University of Innsbruck) for permission to include case 3 in this study and Ema Jaschke, M.D. Kufstein (Austria) for providing care for this patient; Wilfried Kohler, M.D., Department of Otolaryngology II, University of Vienna, for performing audiologic tests in case 2, Mrs Uschi Hornick and Mr Heinz Gaudek for technical assistance, and Mrs Sylvia Hermanek for typing tbe manuscript. REFERENCES 1 Skinner BA, Greist MC, Norim AL. The keratitis, ichthyosis, and deafness (KID) syndrome. Arch Dermatol 1981; 117:285-9. 2 Bums FS. A case of generalized congenital keratodenna with unusual involvement of the eyes and nasal and buccal mucous membranes. J' Cuian Dis 1915; 33: 255-60. 3 Wells RS, Kerr CB. Genetic classification of ichthyosis. Arch Dermatol 1965; 92: r-6. 4 Baden HP. Ichthyosiform Dermatoses. In: Dermaiology in General Medicine (Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds), 3rd edn. McGraw Hill, 1987; 1017-25. 5 Voigtiander V. Hereditare Verhomungsstorungen und Taubheit. Z Hautkr 1977; 52: 1017-25. 6 Taussig LR. Ichthyosis with involvement of the cornea. Arch Dermatol 1939; 40: 504-5. 7 Morris J, Ackerman AB, Koblenzer PJ. Generalized spiny hyperkeratosis, universal alopecia and deafness. Arch Dermaiol 1969; 100: 692-8. 8 Beare JM, Nevin NC, Froggatt P ef al. Atypical erythrokeratoderma with deafness, physical retardation and peripheral neuropathy. Br J Dermatol 1972; 87: 308-14. 9 Wilson FM, Grayson M, Pieroni D. Comeal changes in ectodermal dysplasia. Am J Ophthalmol 1973; 75: 17-25. 10 Rycroft RJG, Moynahan EJ, Wells RS. Atypical ichthyosiform erythroderma, deafness and keratitis. Br J Dermatol t976;94: 211-17. 11 Cremers CWRJ, Philipsen VMJG, Mali JWH. Deafness, ichthyosiform erythroderma, comeal involvement, photophobia and dental dysplasia, J Laryngol Owl 1977; 91: 585-7. 12 BrittonHjLustigJ,Thompson BJ era/. Keratosisfollicularisspinulosadecalvans. Arch Dermatol 1978; 114:761-4. 13 Silvestri DL. Ichthyosiform dermatosis and deafness. Arch Dermaiol 1978; 114: 1243-4. 14 Senrcr ThP, Jones KL, Sakati N, Nyhan WL. Atypical ichthyosiform erythroderma and congenital neurosensory deafness—a distinct syndrome. J Pediarr 1978; 92: 68-72. 15 Cram DL, Resneck JS, Jackson WB. A congenital ichthyosifonn syndrome with deafness and keratitis. Arch Dermaiol 1979; 115: 467-71. 16 Van Everdingen JJE, Rampen FHJ, van der Schaar WW. Normal sweating and tear production in congenital ichthyosiform erythrodenna with deafness and keratitis. Acta Dermatovener 1981; 62: 76-7. 17 Grob JJ, Breton A, Bonafe JL et al. Keratitis, ichthyosis and deafness (KID) syndrome. Vertical transmission and death from multiple squamous cell carcinomas. Arch Dermatol 1987; 123: 777-82. 18 Pincus StH, Thomas IT, Clark RA et al. Defective neutrophil chemotaxis with variant ichthyosis, hyperimmunoglobuiinemia E, and recurrent infections. J Pediatr 1975; 87: 908-11. 19 Baden HP, Alper JC. Ichthyosiform dermatosis, keratitis and deafness. Arch Dermatol 1977; 113: 1701-4. 20 Jurecka W, Aberer E, Mainitz M et al. Keratitis, ichthyosis, and deafness syndrome with glycogen storage. Arch Dermatol 1985; 121: 799-801. 21 Lancaster L, Jr, Fournet LF. Carcinomaof the tongue in a child: report ofa case. J'Ora^AfajoV/d/acSwty 1969; 17: 269-70. 22 Carey AB, Burke WA, Park HK. Malignant fibrous histiocytoma in keratitis, ichthyosis, and deafness syndrome. J Am Acad Dermaiol igSS; 19: 1124-6. 23 Baden HP, Bronstein BR. Ichthyosiform dermatosis and deafness. Report of a case and review of the literature. Arch Dermatol 1988; 124: 102-6. 24 Madriaga J, Fromowitz F, Phillips M et al. Squamous cell carcinoma in congenital ichthyosis with deaihess and keratitis. A case report and review of the literature. Cancer t9S6; 57: 2026-9. 25 Eriksen L, Cormane RH. Oral retinoic acid as therapy for congenital ichthyosiform erythroderma. BrJ Dermatol 1975; 92: 343-526 Peck GL, DiGiovanna JJ. Retinoids. In: Dermatology in General Medicine (Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, edsj, 3rd edn. McGraw Hill, 2583-609.
