Hypomelanosis of I to (Incontinent ia Pig men t i Ac h ro m i a n s) THERE are a number of disorders affecting the nervous system and skin. The neurocutaneous disorders include such well known conditions as neuro- fibromatosis and tuberous sclerosis. Hypomelanosis of Ito', although one of the rarer syndromes, is the third most frequent neurocutaneous disease'.

Clinical features GLOVER er al.' report 19 children with this syndrome. 13 were developmentally delayed, one was deaf with associated speech disorder and nine had a history of seizures. Hemihypertrophy occurred in four patients, syndactyly in three and scoliosis in one. There were ocular abnormalities in three patients, one with severe myopia, one with bilateral microphthalmos, and one with retino- pathy and impaired vision. 1 1 of the children had abnormal encephalograms, and nine had abnormal brain scans. Four of these showed findings suggestive of abnormal neuronal migration, three evidence of cerebral atrophy, one asymmetry of the cerebral hemispheres, and one an infarct in the left lentiform nucleus.

Hypopigmentation was present from birth in two children, and in the rest it was

noticed by the age of 18 months; usually before. The lesions become less apparent with time. The hypopigmentation was macular, in a pattern of whorls, streaks and patches; it was sometimes difficult to see against white skin, unless there was more than one shade. This may account, in part at least, for the excess of reported patients among black people4. Ultraviolet light (Wood's lamp) reveals the extent of the lesions much more clearly'. In 10 patients, neuroIogica1 and musculo- skeletal abnormalities appeared before the hypopigmentation. The lesions often showed a sharp midline cut-off, and were sometimes more marked on one side than the other. Hypopigmentation can appear anywhere with the exception of the palms, soles, scalp and mucous membranes, and may be associated with hypohydrosis6.

Parhology and associated abnormalities The hypopigmented lesions are the result of a decreased number of melanocytes, as well as a decrease in the number and size of melanosomes7. The striking pattern of stripes, streaks, whorls and patches is thought to be the result of random distribution of two clones of cells along the primitive streak early in embryo- genesis, and from their subsequent migration. The paths of migration, known as Blaschko lines, were originally identified by observing the pattern of linear naevoid anomalies'. A variety of x-linked gene defects with dermal lesions which follow these lines suggests a causal relationship with lyonization, although somatic mutations and chimerism can give rise to the same linear patterns. In women affected by x-linked skin dis-

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: orders, the lines of Blaschko visually represent the clonal proliferation of two

2 functionally different populations of cells 2 during early embryogenesis of the skin;

they are not of dermal origin, but from a non-random developmental pattern3- '.

The histopathological findings in the nervous system are not specific, and

.consist of pachygyria, multiple grey matter heterotopias and basal ganglia dysplasia in the cerebrum; as well as atrophy, heterotopias, Purkinje cells in the granular layer, and an increase of Bergmann glia in the cerebellum. Postmortem examination of a child aged 22 months with proven hypomelanosis of Ito revealed severe neuronal migrational defects which altered the architecture of the cerebral cortex white matter. There were many grey matter heterotopias. Embryological migration of both melano- blast's from the neural crest and cortical neurons occurs in the second trimester, suggesting a common mechanism for the skin and brain lesions''. Similar histo- logical changes have been found in tuberous sclerosis, but this disorder should easily be diagnosed by the finding of calcified subependymal nodules.

Additional skin abnormalities are often found, and include cafe-au-lait spots, angiomatous naevi, naevus marmorata, and mongolian blue spots. There can be heterochromia of the iris or hair, alopecia, hypertrichosis, and white or greyish-white trichorrexia and mottled hair. Skin lesions may disappear with time.

Abnormalities associated with the skin and neural lesions are mental impairment (more than 60 per cent of patients), autistic behaviour and hyperactivity. Seizures are frequent, especially in the presence of mental impairment. The seizures can take a number of forms, in particular infantile spasms or other types of myoclonus; and the epilepsy and retarded development can probably be explained by abnormal cell migration. The extent of the hypopigmentation does not correlate with the severity of the neurological disease, or the neuro- radiological or histological findings. The severity of the neurological disorder seems to be more closely associated with the early onset of symptoms'.

There are a number of other associated

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disorders which occasionally occur. Among these are macrocephaly, micro- cephaly, hemiparesis, hemihypertrophy, hypotonia, disturbances of gait, scoliosis, spina bifida occulta, facial anomalies and coarse facies, and abnormalities of the teeth and eyes. The teeth can be conical with partial anodontia, dental hypo- plasia, defective enamel, and with hamartomatous cuspids protruding from the dental crowns of the permanent teeth. Ocular anomalies include strabismus, nystagmus, retinal pigmentary abnor- malities, tessellated fundus, pupillary dislocation, choroidal atrophy, opaque cornea, optic atrophy, and micro- phthalmia". Deafness has been reported, so that routine hearing tests should be carried out on these patients". ZAPELLA" has reported a pair of monozygotic and a pair of dizygotic twins with autism and hypomelanosis of Ito. The association between these two conditions raises the possibility of a higher incidence of single- gene conditions among cases of autism with a known genetic basis. I t is postu- lated that the link between the conditions may be a dysfunction of melatonin.

Investigation No consistent electroclinical associations are found in this syndrome, although there are some between the presence of abnormal rhythmic EEG activity and the radiological appearances of neuronal migration defects. The possibility is raised that there may be a distinctive group of affected children who present with intractable seizures of early onset and have a neural migration defect; and certainly have a poor prognosis. The severity of the EEG changes have some relationship to the degree of neurological involvement, and it is possible that abnormal rhythmic activity may indicate a defect of migration. On the other hand, there does not seem to be any relationship between the severity of the skin manifestations and the EEG abnor- malities, except possibly in one patient reported by ESQU~VEL et aI.I4. In this case there were runs of irregular high- amplitude spikes and sharp waves over different regions of one or other hemisphere, associated with multifocal migratory clonic seizures. The CT scan

showed abnormal tissue density in the frontal lobes down to the region of the anterior horns of the ventricles, which were underdeveloped.

CT scans can show atrophy or hypoplasia of the cerebrum and cerebellum, ventricular dysplasia, por- encephaly, enlargement of the cerebral hemisphere, abnormal density of the white matter, and defects of neuronal migration. MR1 confirms parenchymal lesions affecting the white and grey matter, and can sometimes show abnormalities of neural migration when the CT scan does not’. Cortical hemiatrophy and contralateral pre- dominance of hypopigmentation, and cortical defects and contralateral limb and trunk asymmetries have been recorded”.

Inheritance Various forms of inheritance have been proposed. Autosomal dominant inheri- tance and x-linked dominance-often lethal in the male, which explains the female predominance-have been reported12. In addition, the family history can be consistent with x chromosome inactivation, according to the Lyon hypothesis, or with x chromosome translocation; and new mutations may occur16. It is also suggested that there ma be no hereditary basis for this condition .

A balanced translocation bet ween chromosomes 2 and 8 has been reported by MILLER and PARKER”, but this finding may be coincidental, although a small deletion cannot be excluded. A mosaic trisomy 18 was found in one patient by GOLDEN and K A P L A N ~ . Chromosome mosaicism has been shown in dermal fibroblasts, which could explain the hypopigmentation as being the result of two populations of melanocytes with different pigment-producing potentials. However, this is unlikely to be the only explanation3. It is thought that the gene assignment for Bloch-Schulzberger syndrome may be to Xpl 1, and TURLEAU et 41.’’ report a child with hypomelanosis of Ito with mosaicism for a microdeletion of the proximal region of 15q similar to that observed in Prader-Willi syndrome. This may be a gene assignment for Ito’s disease, or may represent a non-specific

Y

marker for mosaicism”. Clinical descrip- tions show considerable overlap between hypomelanosis of Ito and diploid/triploid mixoploidy, and although this may account for only some cases of the former condition, it may sometimes justify a skin biopsy’*. I t is tempting to suppose a direct interaction between the hypo- pigmentation and the chromosomal aberration, but this seems unlikely since the skin lesions are due to abnormalities of melanocytes of neuro-ectodermal origin, while the chromosomal mosaic has been revealed in fibroblasts of mesodermal origin”. Also, as stated, pigmentary anomalies with a pattern resembling Blaschko lines are indicative of two cell populations with different pigment potential, suggesting an under- lying mosaicism of chimerism’’.

Differential diagnosis Hypomelanosis of Ito should be distinguished from incontinentia pigmenti or Bloch-Schulzberger syndrome, which is probably transmitted as an x-linked dominant gene that is prenatally lethal in males”. In this condition there are erythematous, papular, vesicular or bullous lesions in infancy, which last for a short period to be replaced by pustular, verrucous or keratotic rashes. Then pigmented lesions appear, although in some children they are not preceded by other skin manifestations. Gradually all rashes resolve, and are usually absent by adult life2’. It can be said that the cutaneous lesions of hypomelanosis of Ito resemble those of Bloch-Schulzberger disease, but in a negative image”. Histologically, there is absent or decreased melanin in the basal epidermal cells, with an accompanying excess in the dermis, suggesting a leakage or incontinence of the basal cells. There are a number of associated disorders, such as seizures, mental retardation, encepha- :apathies, skeletal anomalies, eye lesions which can lead to severe visual loss, and hair and dental abnormalities”.

Other skin disorders that have to be considered in the differential diagnosis include tinea versicolor, vitiligo, pie- baldism, tuberous sclerosis, naevus anaemicus, poikiloderma, xeroderma pigmentosum and hypomelanotic naevi.

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Hypomelanotic naevi are apt to cause most difficulty, although the areas of cutaneous hypopigmentation are usually single and well defined. I t is possible that this disorder reflects a somatic mutation occurring later in embryogenesis than the events leading to the lesions of hypomelanosis of Ito3.

In a disease only recently described, carbohydrate-deficient glycoprotein syn- drome, there is a complex carbohydrate defect in glycoproteins. The most marked and constant change is a deficit in transferrin in the serum, CSF and liver. Other findings suggest a defect in macro- moleclar metabolism, and there may be a primary abnormality in the biosynthesis, processing or transport of glycoproteins”. I t presents in a variety of forms. Infants affected by type 111, described by SIBLER et were floppy, with a dystrophic appearance and retarded development. Apart from optic atrophy and infantile spasms, there were depigmented skin areas resembling those seen in hypomelanosis of Ito.

Conclusion Hypomelanosis of Ito may not be that uncommon, especially as the diagnosis may be missed if the skin is not examined with a Wood’s lamp. Further research is needed on the mode of inheritance, but this must depend on the diagnosis of more instances of the condition. This in turn may lead to effective prevention and treatment .

Huntly wood, 3 Styal Road, Wifmslow, Cheshire SK9 4AE, UK.

NEIL GORDON

References I . 110, M. (1952) ‘Studies of melanin XI.

lncontinentia pigmenti achromians. a singular case of naevus depigmentosus systematicus bilateralis .’ Journal of Experimental Medicine.

2. Lancet (1992) ‘Hypomelanosis of 110.’ Lancet, 339, 650-651. (Annotation.)

3. Glover, M. T.. Brett. E. M., Atherton. D. J. (1989) ‘Hypomelanosis of 110: spectrum of the disease.’ Journal of Pediatrics. 115, 75-80.

4. David, T. J . ‘Hypomelanosis of Ito: a neuro- cutaneous svndrome.’ Archives of Disease in

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Childhood. 56, 789-800. 5. Ardrnger, H. H., Bell, W. E. (1986) ‘Hypo-

melanosis of 110. Wood’s light and magnetic

resonance imaging as diagnostic measures.’ Archives of Neurology, 43, 848-850.

6. Golden. S. E.. Kaplan, A. M. (1986) ‘Hypo- melanosis of lto: neurologic complications.’ Pediatric Neurology, 2, 170- 174.

7. Hamada, T., Seito, T., Sugai, T., Marita, L. (1967) ‘Incontinentia pigmenti achromians (Ito).’ Archives of Dermarology, 96, 673-676.

8. Jackson, R . (1976) ‘The lines of Blascho: a review and reconsideration .’ British Jortrnul of Dermatology, 95, 349-360.

9. Happle. R . (1985) ‘Lyoniration and the lines of Blaschko.’ Human Genetics, 70, 200-206.

10. Ross, D. L., Liwnicz, B. H.. Chun. R. W. N., Gilbert, E. (1982) ‘Hypomelanosis of Ito (incontinentia pigmenti achromians)-a clinico- pathologic study: macrocephaly and gray matter heterotopias.’ Neurologv, 32, 1013-1016.

I I . Hamada. K., Tanaka. T., Ohdo, S.. Hayakawa, K.. Kikuchi, I . , Katsuya, H. (1979) ‘In- coniinentia pigmenti achromians as part of ! neurocutaneous syndrome: a case report. Brain and Development, I , 313-317.

12. Griebel, V., Krageloh-.Mann, I . , Michaelis, R. (1989) ‘Hypomelanosis of Ito-repor! of four cases and survey of the literature. Neuro- pediatrics, 20, 234-237.

13. Zappella. M. (1993) ‘Autism and hypomelanosis of I t 0 in twins.’ Developmental Medicine and Child Neurology, 35, 826-832.

14. Esquivel. E. E., Pitt, M. C . . Boyd, S. G. (1991) ‘EEG findings in hypomelanosis of 110.’ Neuropediatrics, 22, 2 16-2 19.

15. Miller, C. A,. Parker, W. D. (1985) ‘Hypo- melanosis of Ito: association with a chromosomal abnormality.’ Neurology, 35,

16. McKusick, V. A. (1986) Mandelian Inheritance in Man. Baltimore. MD: Johns Hopkins University Press.

17. Turleau, C.. Taillard, F., de Bazignan, M. D., Delpine, N., Desbois, J . C.. de Grouchy, J . (1986) ‘Hypomelanosis of I t 0 (incontinenria pigmenti achromians) and mosaicism for a microdeletion of l5ql.’ Human Genetics, 74,

18. Donnai, D., McKeown, C., Andrew, T.. Read, A. P. (1986) ‘Diploid/triploid mixoploidy and hypomelanosis of 110.’ Lancer, 1, 1443-1444.

19. RON, H.-D., Ulmar. R., Haneke, E. (1986) ‘Hypomelanosis of I t 0 and chromosomal mosaicism in fibroblasts.’ Lancer, I , 343. (Letter. )

20. Thomas, I . T., Frias, J . L. (1986) ‘Hypo- melanosis of It0 and chromosomal mosaicism in fibroblasts.’ Lancer. 1, 343. (Letter.)

21. Aicardi. J. (1992) Diseases of fhe Nervous System in Childhood, Clinics in Develop- mental Medicine. Nos. 115-118. London: Mac Keith Press.

22. Carney, R. G. (1976) ‘Incontinentia pigmenti. A world statistical analysis.’ Archives of Dermatology, 112, 535-542.

23. Stibler. H., Westerberg, B., Hanafeld. F.. Hagberg. B. (1993) ‘Carbohydrate-deficient glycoprotein (CDG) syndrome-a new variant, type 111.’ Neuropediatrics. 24, 51-52.

24. Hagberg. B., Blennow, G., Stibler, H. (1992) ‘The birth and infancy of a new disease: the carbohydrate-deficient glycoprotein syndrome.’ I n Fukuyama, Y., Suzuki. Y ., Kamoshita, S., Casaer. P. (Eds.) Feraland Perinatal Neurology. Basel: Karger.

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