Ital. J. Neurol. Sci. 7: 233-242, 1986
Ichthyosis accompanied by neurological symptoms with special reference to epilepsy Quattrini A.*, Ortenzi A.*, Silvestri R.*, Paggi A.*, Fronzoni M.*, Pace D.P.**, D'Angelo I.***, Ardito S.*, Sgriccia S.* *Centro Epilessia, Ospedale Regionale Torrette,Ancona **Istituto di Genetica Medica, Universit°li Studi di Ancona ***Divisione di Dermatologia, Ospedale Regionale Umberto I, Ancona
5patients with ichthyosis had a neurological accompaniment: epilepsy in 4, congenital palpebral ptosis, facial pain and neurosis in 1. In one patient epilepsy was combined with multiple malformations (normal dwarfism, prematurely oldface, skeletal abnormalities) and oligophrenia. There was considerable variability genetically: 2 sporadic cases, 1 with X-linked transmission, 1 with autosomal dominant and 1 with apparent autosomal recessive heredity. In one case the coexistence of gIucose-6-phosphate dehydrogenase deficiency provided proof of Xlinked transmission. Further study of larger case-series is needed for a better definition of the nosographic and genetic aspects of non blastomatous neuroectoz dermatoses in which ichthyosis figures. Key-Words: Ichthyosis -- neurological symptoms -- epilepsy
Introduction Neuroectodermatoses fall into two main categories according to the presence or absence of blastoma potential. The first category comprises the phakomatoses [8] while the second embraces many other nosological entities that make diagnostic differentiation difficult because of the myriad associations between neurological, dermatological and internist associations [3,7,10,13,15,17]. Ichthyosis is a skin disease present in a large number of these conditions. None of the classifications of the ichthyoses now meets with unanimous consent [5,9,12]. Some classifications rely chiefly on the histological findings, others on the clinical features and yet others concentrate on the genetic aspect. Ichthyoses may be classified etiologically as congenital or acquired, in terms of course as benign or malignant, and in terms of association with other symptoms as unassociated, associated with
neurological disorders, associated with other disorders (endocrine, ocular, auditory, skeletal and so on) and associated with neurological and internist disorders combined. Acquired ichthyoses, localized and diffuse, may be secondary to drugs (allopurinol, butyrophenones, etc.) or to chronic deficiency diseases (leprosy, pellagra, etc.) or to paraneoplastic diseases (associated with lymphomas, reticulosarcomas, bronchial carcinomas and so forth) [12]. The principal nosological forms in which ichthyoses present in association with neurological disorders are: Rud syndrome [14], Sj~gren-Larssen syndrome [15], Refsum disease [13], Tay syndrome [17], Conradi-H0nermann syndrome [10], Netherton syndrome [11], the K I D syndrome [16] and multisystem triglyceride storage disorder [1]. In these syndromes hyperkeratosis, as a rule ichthyosiform, of variable severity, is associated with -- usually severe -- neurological symptoms; they are frequently combined with changes in other or233
The Italian Journal of Neurological Sciences
gans and systems, outside the common ectodermal origin of the skin and nervous system. Approaching this is the De Sanctis-Cacchione syndrome, which combines short but proportional stature, microcephaly, photophobia and neurological troubles with xeroderma pigmentosum [4]. Patients and method
An association between ichthyosis and neurological symptoms was found in 5 cases taken from a series of 1350 patients followed at the Epilepsy Center of Torrette Regional Hospital (Ancona). All 5 patients underwent the following investigations: 1) pedigree study; 2) clinical and instrumental neurological assessment (EEG, CT, psychometric testing, etc.); 3) internist examinations with special reference to tests for endocrine disease; 4) specialist examinations: oculist, ENT, dermatological and so on; 5) skin biopsy. We report the history, clinical and instrumental data for each of these cases. Case 1 -- Boyaged 10 Principal clinical features: ichthyosis, epilepsy, ]3-thalassemia trait, glucose 6-phosphate dehydrogenase (G6PD) deficiency. Son of nonconsanguineous parents, he presented ichthyosis from early infancy. Born slightly cyanosed due to postmaturity and prolonged labor from primary uterine inertia, the patient presented normal psychophysical development. At the age of 8 he had simple partial seizures, which generalized secondarily, the seizures ceasing after three weeks on CBZ (15 mg/kg daily). After about a year he presented pithiatic episodes with headache, muscular hypotonia, arrested speech and apparent loss of consciousness. The patient was able to bring on these episodes as soon as he tried to speak or cough, or even to order. These symptoms, which did not correspond to any EEG variations, was refractory Fig. 1. Pedigree (~[case I
IV
9
234
I~ EPILEPSY ~ ICHTHYOSIS 9 EPILEPSY AND ICHTHYOSIS
to various drugs (promazine, etc.) but disappeared after about 6 months. Physical examil~ation was normal, as was the IQ. The blood chemistry tests revealed a 13-thalassemia trait and low G6PD values. EEG showed a focus of sharp waves in the fight temporo-occipital region while the background activity was well organized and symmetrical. The CT brain scan was normal. Fig. 1 gives the pedigree, which shows only one case of ichthyosis (maternal grandfather), apart from the proband. Epileptic seizures were found in four collaterals (one female cousin on the father's side and three of the mother's brothers), of whom one had postencephalitic epilepsy and three died before two years of age of status epilepticus. As to the EEG of the immediate family members, the father and elder sister presented bitemporal sharp waves, whereas the mother and brother had normal tracings. All five members of the family presented hematological changes: [3-thalassemia trait in the proband's father, G6PD values below normal limits in the mother and sister and actually deficient in the proband. The search for antigens of the Xg system yielded the following results: father Xg, mother and three children Xg a (Fig. 2). Dermatologically, clinical examination showed diffuse ichthyosis, especially on the extensor surfaces of the arms and legs, but very marked also on the neck and ear flaps; the scales were very dark, of the ichthyosis nigricans type; biopsy of skin from the outer surface of the fight arm yielded a histological pattern consistent with Xlinked ichthyosis (granular layer spared with acanthosis and hyperkeratosis). Figure 3 (A and B) reproduces the photographic documentation of the proband's skin changes. Case 2 - - Woman aged 29
Principal clinical features: ichthyosis, epilepsy,
Quattrini A.: lchthyosis and neurological o,mptoms
parameters were normal; 2) intelligence was mildly subnormal (IQ = 78); 3) cutaneous hyperkeratosis with diffuse ichthyosiform scales, especially on the arms and legs (the histological pattern was that of ichthyosis vulgaris).
\
~ ) l~r] 13THALASSEMIATRAIT ~ ) ~1 G6PDDEFICIENCY ( ~ [ ~ SIDEROPENICANEMIA ( ~ 1"~ Xg~'-SYSTEM ~~ XgSYSTEM Fig. 2. Hematological abnormalities in the pedigree of case I mild oligophrenia. The patient was born postmature, by normal delivery. Her mental development was somewhat retarded and her school performance was very poor. Skin lesions, diagnosed as ichthyosis, were noted right from the first months. At the age of 9 years she began to have generalized tonic-clonic seizures, which occurred monthly and usually in the daytime. Treatment with phenobarbital and later valproate definitely reduced seizure frequency. Married at the age of 25, the patient had two daughters. Clinical examination yielded the following salient points: 1) the various neurological
In the pedigree of figure 4 we find 4 other cases of ichthyosis: one of the father's sisters (who died in childhood of meningoencephalitis), two siblings (a brother and one of two twin sisters) and the firstborn daughter of the proband. One sister, as well as the proband, had presented convulsive seizures and 4 members of the kindred, in addition to the proband, had medium grade oligophrenia (2 twin sisters, one of whom died, one of the father's sisters and a female cousin on the mother's side). Ichthyosis of mild degree was found in the proband, in her first-born daughter and in a brother, and of marked degree in a sister. Epileptic seizures were found not only in the proband but also in a 24 year old sister, who presented only two generalized seizures. E E G changes were found in 6 members of the kindred: in the proband's daughter, in her mother and in two siblings they took the form of mostly sporadic diffuse sharp waves whereas in the proband herself and in the sister who had had two seizures the background activity was slightly but diffusely slowed. Records during sleep (1 st cycle) and after sleep deprivation revealed no further EEG anomalies. In the proband CT showed mild subcortical atrophy on the right side and modest ventricular enlargement, mainly on the right side. Case 3 -- Woman aged 24 Principal clinical features: hyperkeratosis with ichthyosis, prematurely aged face, short but wellproportioned stature, oligophrenia, epilepsy, skeletal abnormalities. Born after prolonged labor with perinatal cyanosis and birthweight 4000 g, the patient had con-
Fig. 3. Dermatologicaljeatures qlcase I
235
The Italian Journal of Neurological Sciences
-T9 III
IV
(~ [ ] ICHTHYOSIS (~ [ ] EPILEPSY ~) [ ] MENTAL RETARDATION Fig. 4. Pedigree o f case 2 vulsions on the third day, which were repeated frequently for some 48 h. Her psychomotor and somatic development were retarded. At the age of 9 she had complex partial seizures several times a month, singly and in clusters, and generalized tonic-clonic seizures 3-4 times a year. This frequency continues unchanged to this day notwithstanding therapy. Clinical examination produced the following salient data; 1) general and endocrine status: short stature with underdeveloped body but normal proportions (height 134 cm and weight 35 kg), prematurely aged face and exophthalmos; poorly developed secondary sex characters and scanty body hair; breasts infantile in shape and ~size with very pronounced nipples; 2) dermatological status: hyperkeratosis of the face and hands, the skin was yellowish, thick and shagreened with ichthyosiform scales and very numerous warts; the hair was very fine, brittle and thin in the occipital region; 3) skeletal findings: pes cavus-varus-supinatus, modest fight convex scoliosis of the spine, high-arched palate, stumpy hands with arachnodactyly; 4) neuropsychic status: medium grade to severe oligophrenia, clumsy coordination of movement, gait somewhat awkward, partly because of the peculiar conformation of the feet. Figure 5 shows the pedigree: the most frequent feature is the presence in the second generation of premature baldness in three brothers, one of whom is the father of the proband. Figure 6 (A and B) illustrates some features of the hands. The X-ray film in A shows the irregular 236
distribution of cortex in the metacarpal and phalangeal bones with a fair degree of osteoporosis and diffuse capsulo-ligamentous alteration. B shows the stumpy hand with a hint of arachnodactyly. The CT brain scan showed modest but diffuse subcortical atrophy, mainly in the left hemisphere. Figure 7 illustrates some of the facial features already described: the prematurely aged face, the patches of hyperchromia, the protruding ears, etc. (A and B). Other investigations, like ECG, routine blood chemistry tests irlcluding electrophoresis of the Hb, tests for metabolic disorders (aminoacids and mucopolysaccharides) proved to be normal. The karyotype (46, XX) was normal too. The head hair, examined both by light and phase contrast microscopy, displayed no noteworthy alterations. Case 4 - - M a n aged 39
Principal clinical features: ichthyosis, palpebral ptosis, facial pains, neurosis. This patient's family history was totally negative for neuropsychiatric disease and his own physiological and previous medical history was negative too. For some years he has had facial pain in the territory of the second division of the trigeminal nerves, mainly on the left side; it is a burning pain that lasts for hours or days at a time and shows little response to various drugs, including CBZ. Right from early childhood the patient has had ichthyosiform hyperkeratosis. The only item to emerge from neurological examination was a left palpebral ptosis which, ac-
Quattrini A. : Ichthyos& and neurological symptoms
+_U7
'
III
Y IV
•)
[]
PROGRESSIVE MYOPIA
(~
[]
EARLY HAIRLESS
~)
[]
ENDOGENOUS DEPRESSION ICHTHYOS S, EPILEPSY AND VARIOUS MALFORMATIONS
Fig. 5. Pedigree o f case 3
A
B
Fig. 6, Radiological and morphologicaljeatures o f the hands" in case 3 cording to the patient and his relatives, has been present from birth. Dermatological examination showed hyperkeratosis with ichthyosiform scales all over the body, but particularly on the extensor surfaces of the limbs, on the abdomen and on the chest; ichthyosis was also present on the neck and on the outer region of the ear flaps, although to a lesser degree. The scales were small, thin and grey. In the pedigree (Fig. 8) we find ichthyosis only in the proband; neonatal convulsions were present in two third-generation twins, who died in status epilepticus, probably due to severe neonatal asphyxia and immaturity. The CT brain scan in the proband was normal,
even after enhancement. Repeated EEG, some for long periods and during sleep, were perfectly normal. Psychiatric investigations (anxiety and depression ratings, MMPI) showed only an anxiety state in a slightly insecure personality. The histological findings on a skin biopsy fragment were compatible with ichthyosis vulgaris. Case 5 -- Girl aged 17
Principal clinical features: ichthyosis, epilepsy, mild mental retardation. This patient was born at term by forceps delivery with fetal distress. In the first month of life the patient presented a non bullous ichthyosiform erythroderma, the erythroderma being mainly on the face and the hyperkeratosis on the extensor sur237
The Italian Journal Of Neurological Sciences
B
Fig. 7. Facialjeatures o f case 3 Fig. 8. Pedigree o f case 4
\
IV
O 238
i
ICHTHYOSIS
N
NEONATAL CONVULSION
Quattrini A. : lchthyosis and neurological symptoms
S
[] ~ EP L ,EpS~
[]
[ ] (~ MENTAL RETARDATqON
[] ~) PARAPARESIS
(~ ICHTHYOSIS
Fig. 9. Pedigree of case 5 faces of all four limbs. Psychomotor development and the first acts of vegetative and relational life were normal. At the age of 13 1Ayears the patient had four complex partial seizures that quickly responded to phenobarbital, which she is still taking. General physical, neurological and internist examinations were normal. The E E G showed normal background activity with bursts of theta waves and asynchronous bitemporal sharp waves; with overbreathing there were bursts of diffuse and synchronous 3-4 c/s spike-and-wave complexes. A radionuclide scan and a CT scan of the brain were normal.
gophrenia in association with spastic paraparesis (a brother of the father, a son of a sister of the mother and a nephew of another of the mother's sisters). Epilepsy as an isolated symptom is present in a son of one of the father's brothers and in one of the mother's brothers. The proband is the only survivor after 9 pregnancies that ended in miscarriage. To facilitate comparison of the 5 cases presented we have tabled all the clinical features for each case (Table I). Discussion
Figure 9 shows the proband's pedigree. Both on the paternal side (a sister of the father) and on the maternal side (daughter of a sister of the mother) there is ichthyosis and again on both sides oli-
None of the cases reported complies strictly with any of the syndromes mentioned at the outset, either because cardinal symptoms are missing or
TABLE I. Clinical features of the 5 cases Case
Age yrs
Sex Type of ichthyosis
Type of epileptic seizures
Neurological signs and symptoms
Psychic status
Other symptoms
1
10
M
X-linked
simple partial with secondary generalization
EEG abnormalities
hyisterical neurosis
prognathis, 13-thalassemia trait, G6PD deficiency, sideropenic anemia
2
29
F
vulgaris
generalized tonic-clonic
EEG abnormalities
mild mental retardation
normochromic anemia
3
24
F
verrucous complex partial erythro-kera- with secondary toderma of generalization face and limbs
EEG abnormalities, pendular nystagmus
severe mental retardation
normal dwarfism, hypogenitalism, exophthalmos, thinning hair, skeletal abnormalities, myopia
4
39
M
vulgaris
--
palpebral ptosis, facial pains
anxiety neurosis
--
5
17
F
vulgaris
complex partial
EEG abnormalities
--
--
= glucose-6-phosphate dehydrogenase
239
The Italian Journal of Neurological Sciences
because symptoms usually regarded as extraneous to these nosological entities are present. Case 1 is remarkable for the association of ichthyosis, epilepsy and hematological abnormalities ([3-thalassemia trait, G6PD deficiency), even though the latter abnormalities never gave rise to clinical symptoms. The association of ichthyosis and epilepsy suggest the confluence in the proband of an epileptic heredity from both maternal and paternal kindreds, although of low expressivity in the pedigree considered. The transmission of ichthyosis by the maternal grandfather may be seen as X-linked, since the proband's mother may have received from him the X chromosome that carries the ichthyosis gene. She in her turn may have transmitted this X chromosome to the proband with consequent hemizygosity and simultaneous manifestation of the disease. This mechanism of transmission is borne out by the study of the Xg blood group, from which it seems likely that the mother is homozygous for Xg a. Our data thus confirm the latest findings in the field of human genetics, namely, that ichthyosis nigricans, because of its connexions with the blood group Xg, has its genetic defect at the end of the short arm of the X chromosome. Further confirmation of this site on the X chromosome comes from the association with the G6PD deficiency, already evidenced by Ziprowski et al [18], although it is not possible to speak of a strict linkage, since the G6PD deficiency gene is located at the end of the short arm of X. As to the clinical classification of this case, it may be classed among the X-linked ichthyotic neurocutaneous syndromes but cannot be pinned down further in nosographic terms. It differs from the classical Rud syndrome mainly in the lack of mental retardation and of other possible manifestations like the absence of endocrine defects. On the other hand, Guazzi et al [6] regarded the combination of ichthyosis and epilepsy without mental deficiency as a partial form of Rud syndrome. The salient clinical features of case 2 are ichthyosis, epilepsy and mild oligophrenia, an association that can, even without other symptoms, be classed as a Rud syndrome [14]. However, a nosographic classification of this kind is hardly satisfactory because the mental retardation in this case was rather modest, whereas the oligophrenia usually reported is severe [2]. The pedigree study showed that the source of the proband's pathology lay in the father's kindred, possibly by an autosomal dominant mechanism. There is some variability in phenotypic expression, which could explain the absence of the disease in the proband's father. This is at variance with previous accounts of the mode of transmission of Rud syndrome, usually defined as autosomal recessive [12]. The rare cutaneous pathology of case 3 seems to bring it closer to the syndromes of Tay [17], Cock240
ayne [3], Progeria [7] and Conradi-Hiinermann [10]. Tay syndrome [17] includes: low birthweight (this does not fit our case), congenital ichthyosis, mental retardation, short stature, ungueal dysplasia, hypogonadism, cataract and so-called trichothiodystrophy, which tends to disappear with age but which anyway was not found in our patient. Cockayne syndrome [3] includes some of the symptoms present in our case: oligophrenia, oldish face and dwarfism (but not, as in our case "normal") but also other features not present in our case: limbs too long and hands and feet too large for stature, deafness, cataract, retinitis pigmentosa. Our case differs also from Progeria syndrome [7] in its lack of the typical elfin face and peculiar skeletal changes (osteolysis of the hands and feet and diffuse osteoporosis). Then there is Conradi-Htinermann syndrome [10] but here again the dwarfism is disproportionate. Thus our case differs in one way of another from all the ichthyosiform neurocutaneous syndromes so far described. In case 4 ichthyosis was combined with congenital left palpebral ptosis, facial pains and neurosis, an association that defies interpretation. But it does confirm that ichthyosis is often accompanied by mild neurological symptoms, perhaps more often than is commonly thought. This assertion is based also on our findings in another group of six cases of ichthyosis in schoolchildren, on whom we are conducting clinical and instrumental investigations. These children have no noteworthy neuropsychic symptoms, the only factor common to them all, apart from ichthyosis, being poor performance at school and modest personality troubles. Although the investigations on these patients have still to be completed, we think they may provide support for the hypothesis that neuropsychic signs, e'~en though minimal, almost always accompany ichthyosis. As to the type ofichthyosis, the clinical and histological evidence in this case speak for ichthyosis vulgaris or simplex [12], otherwise known as ichthyosis nitida or xeroderma [5]. This form is considered to be transmitted as a regular or irregular dominant trait of variable penetrance. Other cases of ichthyosis were not found in the pedigree of our patient, although admittedly, for reasons beyond our control, only three generations were considered. The most striking feature in case 5 is the pedigree with the nine consecutive miscarriages that preceded the proband's birth. It was not possible to investigate this further. Another interesting point about this kindred is that in various subjects, even of the same generation, various symptoms were present, singly or in various associations that in some of them added up to more or less spurious forms of Sjrgren-Larssen syndrome. The mode of transmission in this case might be autosomal recessive.
Quattrini A. : lchthyosis and neurological symptoms
Conclusions
The analysis of our case-series confirms that ichthyosiform hyperkeratosis may be accompanied by a wide range of neurological symptoms of variable severity. Alongside cases with severe neurological damage (especially case 3) were cases with more nebulous neurological symptoms (case 4). Epileptic seizures were found very frequently in the cases studied (in 4 out of 5 subjects) and yet the association of epilepsy with ichthyosis is a rare occurrence, considering that these four patients were the only ones to have presented ichthyosis in a series of 1350 epileptics. We observed considerable variability on the genetic front: two sporadic cases, one case with linked heredity, one with autosomal dominant heredity and one with apparent autosomal recessive transmission. A singular feature of case 1 is the coexistence of a G6PD de-
ficiency with ichthyosis, which supplied certainty of X-linked transmission. This enabled us to give appropriate genetic counselling. It is clear from our study that further genetic investigations are needed to identify the modes of transmission that carry the highest risk. Another point to emerge, in relation to diagnosis, which is based chiefly on the clinical features and on genetic studies, is the value of skin biopsy, internist and biochemical investigations and, from the neurological angle, the value of EEG, CT brain scanning and psychological tests. Although the psychometric findings are not specific, they are nonetheless indispensable for differential diagnosis. Finally, we feel that the whole subject of nonblastomatous neuroectodermatoses associated with epilepsy calls for further study on larger case-series before they can be more adequately defined.
Sommario
Vengono presentati 5 casi di ittiosi con associata patologia neurologica, rappresentata in 4 casi da epilessia mentre in I sono presenti ptosi palpebrale congenita, algie facciali e nevrosi. In un caso all'epilessia si associano anche malformazioni multiple (nanismo armonico, .facies vecchieggiante, anomalie scheletriche) ed oligoj?enia. E stata riscontrata una notevole variabilith per quanto riguarda l'aspetto genetico: due casi sporadici, un caso con modalita di trasmissione tipo X-linked, un caso con ereditarieth autosomica dominante e un caso di apparente trasmissione autosomica recessiva. In un caso la coesistenza di deficit di G6PD con ittiosi ha consentito di individuare con certezza la trasmissione X-linked. Riteniamo necessario lo studio di casistiche pih ampie per una migliore definizione degli aspetti nosografici e genetici della patologia neuroectodermica non blastomatosa in cui compare ittiosi.
Address reprint requests to: Dr. Angelo Quattrini Via Fiume, 1 -- 60020 Ancona
References [1]
A>,GEt.INIC, PHILIPPART M, BORRONE C, BRESOLIN N, CANTINI M, LUCKE S: Multisvstem triglycer-
[7] HUTCHINSONG: Congenital absence of hair and mammary glands with atrophic condition of skin and its appendages. Med Chir Trans, 69:473, 1886. [8]
ide storage disorder with impaired Iong-chain fat O, acid oxidation. Ann Neurol 7:5-10, 1980. [2]
[3] [4]
BENINCAsA-STAGNI E, GIORDANO A, LINTAS A:
Contriburo al problema delle malattie neurocutanee eredoJ'amiliari. (A proposito di 5 casi di ittiosi con oligo/?enia). II Lav Neuropsich, 27:413-430, 1960. Coc KA',YF E A: lchthyosis. In: Inherited abnormalities of the skin and its appendages. Oxford University Press, London, 158,217, 1933. DE SANCTIS C, CA( (HIONE A: L "idiozia xeroderrni-
ca. Riv Sper Freniatria, 56:2, 1932. EBLINGF J, ROOKA: Disorders ofkeratinization. In: Textbook of Dermatology, Rook A, Wilkinson D S, Ebling F J G (Eds), Vol. 2 Blackwell,Oxford, 1253-1314, 1979. [6] " Gu~,zzl G C, BRAVACrIO F, PASCO~FOA, CARLOsl-xGxo S: h'hthyosis and epilep.sy: a peculiar form qf Rudesyndrome. Acta Neurol, 33:208-216, 1978. [5]
[9]
KISSELP, BEUREYJ : Les g~no-neuro-dermatoses. V1II Congrbs des Dermatologistes de Langue Fran-
qaise. Nancy, 3: 273-320, 1953. KOBLENZERP J: Skin. In: Genetic disorders involving various systems. 1:269-327, 1982.
[10] LANGE H, KEMPERDICK H: Chondrodysplasiapunc-
tata. P~idiatPrax, 14:671, 1974. [11] NETHERTONC W: A unique case of trichorrhexis nodosa "Bamboo Hairs". Arch Derm Syph (Chic.), 78: 483-487, 1958. [12] PUISSANTA, BEYLOTC: Ichthyoses et dtats ichthyosiformes. In: Encycloprdie Mrdico-Chirurgicale. Dermatologie. Masson, Paris, 12605A10, 1972. [13] REFSUMS: Heredopathia atactica polyneuritiformis : a familial syndrome not hitherto described. Acta Psychiatr Neurol Scand, 21 : 38, 1946. [14] RUD E: Et tilfaelde af infantilisme med tetani, epilepsi, polyneuritis, ichthyosis og anaemi af pernicios type. Hospitalstidende 70: 525-538, 1927.
241
The Italian Journal of Neurological Sciences
[15] SJOGRENT, LARSSONT: Oligophrenia in combination with congenital ichthyosis and spastic disorders. A clinical and genetic study. Acta Psychiatr Neurol Scand 32: suppl. 113, 1957. [16] SKINNER B A, GRUST M C, NORINS A L: The Keratitis, Ichthyosis and Deafness (KID) syndrome. Arch Dermatol, 117: 285-289, 1981. [17] TAY C H: Ichthyosiform erythroderma, hair shaft ab-
242
normalities and mental and growth retardation. A new recessive disorder. Arch Dermatol 104: 4-13, 1971. [18] ZIPROWSK1 K, FEINTEIN A, ADAM A, SANGER A, RACE R R: A genetic study of X-linked ichthyosis in Israel. In XII1 Congressus Intemationalis Dermatologiae, Springer (Ed.), Berlin, Heidelberg et New York, vol. 1: 562-565, 1968.