Hypomelanosis of Ito

55.1 Clinical Features

and Laboratory Investigations Hypomelanosis of Ito (HMI), formerly also called in- continentia pigmenti achromians, does not represent a distinct entity but is a symptom of many different states of mosaicism. HMI is characterized by unilater- al or bilateral hypopigmented whorls, streaks, and patches. The abnormal pigmentation follows Blaschko lines. The Blaschko lines have a bizarre fountain-like pattern on the back, whorls on the abdomen and lin- ear stripes on the limbs. Zones of hypomelanosis are easily seen in patients with a darker skin, but to see the zones in patients with a fair skin the use of Wood’s light may be necessary. In most patients the zones are apparent at birth or within the first year of life. The mucous membranes are spared. The hypopigmented whorls represent the “negative pattern” of the hyper- pigmented lesions seen in incontinentia pigmenti type II, an X-linked disorder that is lethal for males.

Another difference with incontinentia pigment type II is that neonatal inflammatory skin abnormalities are lacking in HMI.

HMI is a nonspecific marker for genetic or chro- mosomal mosaicism in persons with a sufficiently dark skin to show lighter patches. Most cases are spo- radic, but autosomal dominant inheritance is evident in some. Incontinentia pigmenti type I is a subtype of hypomelanosis of Ito, associated with an X chromo- some/autosome translocation involving band Xp11.

Abnormalities of the eyes, hair, teeth, muscu- loskeletal system, heart, and CNS occur in some of the patients with HMI. Hypopigmented areas can be ob- served in the iris and the retina. Corneal opacities, macrophthalmia, microphthalmia, strabismus, epi- canthal folds, choroidal atrophy, and optic nerve hy- poplasia may occur. Abnormalities in hair color, alopecia, hypertrichosis, and trichorrhexia may be observed. Fingernails may be abnormal. Numerous types of dental dysplasia may be present. Macro- cephaly is relatively common; microcephaly is less frequent. The face may be asymmetrical. Unilateral hypertrophy or hypotrophy of the body or part of the body may be present. Other abnormalities observed include hypertelorism, bifid uvula, cleft palate, small stature, scoliosis, clinodactyly, and syndactyly. Con- genital cardiac abnormalities and unilateral kidney aplasia may be present. Occurrence of a tumor is a rare observation, and if present, it is most often be-

nign. CNS abnormalities are frequent and these are highly variable. Neurological impairment can be quite severe with hemimegalencephaly or migra- tional defects, leading to intractable seizures and seri- ous mental and motor handicap. About 80% of the patients have mental retardation, which varies from mild to profound. Autism is seen in some patients.

HMI has been associated rarely with vascular abnor- malities such as moyamoya syndrome and intracra- nial arteriovenous malformations. If a parent is affected, he or she may only have cutaneous abnor- malities and no neurological problems, whereas the offspring has evident neurological signs.

In patients with HMI chromosome mosaicism is often restricted to the skin, while blood karyotypes may be normal. For this reason skin fibroblast chro- mosome analysis is recommended. Mosaicism has also been found in keratinocytes obtained from the hypopigmented areas of the skin. The use of FISH facilitates the determination of the origin of the chro- mosomes involved and the extent of the mosaicism when one is detected.

55.2 Pathology

Some patients with HMI may have major brain abnormalities, including hemimegalencephaly and migrational abnormalities. The pathology of these abnormalities is not reviewed here. The pathological correlate of the white matter abnormalities observed relatively frequently in HMI is deficient myelination and gliosis.

55.3 Pathogenetic Considerations

HMI is a manifestation of etiologically heterogeneous conditions, the common factor being chromosomal or genetic mosaicism. A mosaic is defined as an or- ganism composed of two (or more) genetically differ- ent populations of cells originating from a genetical- ly homogeneous zygote. The mosaicism either in- volves a chromosomal abnormality or a gene muta- tion. The chromosomal mosaicism includes an array of different abnormalities: diploid/triploid mo- saicism, diploid/tetraploid mosaicism, mosaicism for trisomies, unbalanced translocation between auto- somes or an autosome and the X chromosome, chro-

Hypomelanosis of Ito

Chapter 55

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mosomal deletions, and ring chromosomes. In the X-chromosome, band Xp11 is involved. HMI due to Xp11 alteration is caused by functional or genetic mosaicism. Functional mosaicism results from the Lyon effect of X inactivation.

Mosaicism can be recognized most easily in the skin, which exhibits patterns of differences in pig- mentation following the Blaschko lines. The different degrees of pigmentation of the skin represent differ- ent cell populations. The abnormal cell line is con- fined to the skin with abnormal pigmentation; the normal skin contains almost only normal cells. It has been hypothesized that the genetic and chromosomal abnormalities result in abnormalities of pigmenta- tion because of altered expression of genes in the pig- mentary pathway. Such genes may be present in dif- ferent regions of multiple chromosomes.

55.4 Therapy

No specific treatment is available.

55.5 Magnetic Resonance Imaging

In many patients with HMI, MRI of the brain is nor- mal. Some patients with HMI have major CNS abnor- malities, including migrational abnormalities and hemimegalencephaly. The migrational abnormalities may consist of cortical dysplasia or neuronal hetero- topias. In hemimegalencephaly, the enlarged hemi-

sphere is dysplastic with a larger ventricle, a thick- ened, pachygyric or polymicrogyric cortex, and fre- quently heterotopic neurons in the white matter. Var- ious other abnormalities have been found, including agenesis of the corpus callosum, asymmetrical or symmetrical ventricular dilatation, focal cerebral at- rophy with porencephalic ventricular dilatation, hemiatrophy, diffuse cerebral atrophy, cerebellar hy- poplasia or atrophy, vascular abnormalities, and, rarely, a tumor.

More subtle brain abnormalities in HMI consist of irregular, multifocal, and confluent abnormalities in the periventricular and deep white matter, usually with increased perivascular spaces within and, to a lesser extent, also outside these areas (Fig. 55.1). In some patients, enlarged perivascular spaces are seen without associated white matter signal abnormalities.

The enlarged spaces may also involve the corpus cal- losum. The increased perivascular spaces are best seen on FLAIR images (Fig. 55.1). The white matter abnormalities are often bilateral but may be asym- metrical in distribution. They are static and probably reflect white matter gliosis and focal myelination de- fects.

Presence of brain abnormalities in HMI appears to be associated with an enhanced frequency of neuro- logical problems. Major malformations are associated with a major handicap. White matter abnormalities with enlarged perivascular spaces are more common- ly seen in patients with a mental handicap, although they have also been observed in HMI patients with a normal cognitive function.

Chapter 55 Hypomelanosis of Ito 410

Fig. 55.1. A 5-year-old boy with HMI, mental retardation, and macrocephaly. The sagittal (first row) and axial (second and third row) T

-weighted images show extensive, partly multifo- cal and partly confluent abnormalities in the cerebral white matter.The posterior fossa structures are spared.The FLAIR im-

ages (fourth and fifth row) allow distinction between enlarged perivascular spaces with a low signal intensity and gliotic white matter with a high signal intensity. Courtesy of Dr. S.

Blaser, Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, Canada

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55.5 Magnetic Resonance Imaging 411

Fig. 55.1. (continued).

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