Incontinentia Pigmenti

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56.1 Clinical Features

and Laboratory Investigations Incontinentia pigmenti (IP), formerly called inconti- nentia pigmenti type II or Bloch–Sulzberger syn- drome, is an X-linked dominant disorder that is usu- ally fatal prenatally in males. Fifty-five percent of the patients have a family history of the disease; the rest of the cases are caused by spontaneous mutations.

So-called incontinentia pigmenti type I is unrelated to incontinentia pigmenti type II and is in fact a sub- type of hypomelanosis of Ito, associated with an X chromosome/autosome translocation involving band Xp11. It has an X-linked dominant mode of inheri- tance. In contrast to incontinentia pigmenti type II, the typical neonatal inflammatory skin abnormalities are lacking. Incontinentia pigmenti type I is dis- cussed in Chap. 55.

Affected females display skin abnormalities in four stages: (1) perinatal inflammatory vesicles, (2) verru- cous patches, (3) hyperpigmentation, and (4) dermal scarring. In IP the pigmentary disturbance is a sort of self-tattooing. The lesions of the first phase are pre- sent at birth or appear within the first 2 weeks of life in 90% of the patients, although they may also appear later in infancy or childhood. They are erythematous, macular, papular, vesicular, and bullous, and suggest an inflammatory condition of the skin. Lesions of the second stage, appearing between 2 weeks and several months of life, are pustular, lichenoid, verrucous, ker- atotic, and dyskeratotic. The third stage is character- ized by development of pigmentation, mainly at the sites of the earlier lesions. In the fully developed dis- ease, the skin shows swirling patterns of melanin pig- mentation, especially on the trunk, with a “marble cake” appearance. The pigmentary abnormalities usually disappear by the age of 20 years. The fourth stage is characterized by atrophic scarring. Hypome- lanotic macules, most often located over the calves, may be the only dermatological indication of IP in adulthood. Late recurrences of the first-stage inflam- matory lesions are uncommon and are usually pre- ceded by an infectious episode.

IP may be associated with a variety of abnormali- ties of the eyes, teeth, and skeleton. Dystrophy of the nails is frequent but usually mild. Any of the cuta- neous stages of IP may involve the scalp.Alopecia sec- ondary to scarring is frequent. Malformed teeth, hy- podontia, or adontia may occur. Ocular abnormalities

include cataract, strabismus, retinal pigmentary ab- normalities, retinal detachments, infarction, vitreous hemorrhage, microphthalmia, and optic atrophy.

The brain is affected in 30–50% of the patients, causing mental retardation, spasticity (hemiplegia or quadriplegia), cerebellar ataxia, and seizures. The head circumference is usually normal at birth, but patients may develop microcephaly. Some of the patients have signs of serious encephalopathy in the neonatal period, with intractable seizures suggestive of viral encephalitis. Acute-onset stroke has been observed occasionally in infants and children with IP.

Patients with structural brain abnormalities and neonatal seizures are at greater risk of motor and mental impairment.

In IP, laboratory studies usually reveal eosinophil- ia in the blood in the neonatal period. The disease is caused by mutations in the NEMO gene, located on chromosome Xq28. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP display extremely skewed X inactivation, which can be demonstrated in peripheral blood leukocytes.

56.2 Pathology

Pathological findings in IP are highly variable and dependent on the stage of the disease. Fresh hemor- rhagic necrosis within the cerebral white matter with perivenous and capillary hemorrhage, vascular con- gestion, edema, and inflammation surrounding the hemorrhage is seen in the early stages. The gray mat- ter may also be affected, but usually to a lesser extent.

In the more chronic stages, ulegyria, cystic changes in the cerebral white matter, neuronal loss, and gliosis are found.

56.3 Pathogenetic Considerations

Mutations in the gene NEMO, located on chromo- some Xq28, cause IP. IP is allelic with ectodermal dys- plasia, an- or hypohidrosis, and immunodeficiency, a disease caused by different mutations in the same gene. NEMO stands for nuclear factor (NF)-k-B essen- tial modulator. The gene is also called IKBKG, which stands for inhibitor of k (kappa) light polypeptide gene enhancer in B cells, kinase of, gamma (g). NEMO

Incontinentia Pigmenti

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is essential for NF-k-B activation. Activated NF-k-B normally protects against tumor necrosis factor alpha (TNF-a)-induced apoptosis.

The most common mutation in IP is a genomic rearrangement resulting in a large deletion within the NEMO gene. This rearrangement, which occurs dur-

ing paternal meiosis, is responsible for 80% of the new mutations. This mutation results in a lack of NF-k-B activation, which leads to an extreme suscep- tibility to proapoptotic signals, leading to embryonic death in males and extremely skewed X inactivation in females with IP. The remaining mutations are small

56.3 Pathogenetic Considerations 413

Fig. 56.1. Female neonate, 3 days old, with IP. She has signs of a devastating encephalopathy and vesicular skin lesions. Note the extensive damage to large parts of the cerebral white matter and cortex, more seriously on the left than on the right.

The lesions have a swollen aspect. The high signal on the

T1-weighted images (third row) indicates hemorrhagic necrosis. Courtesy of Dr. N. Wolf, Department of Pediatric Neurology, and Dr. A Seitz, Department of Neuroradiology, University Hos- pital Heidelberg, Germany

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duplications, substitutions, and deletions. In surviv- ing males with IP, somatic mosaicism or a 47,XXY karyotype with skewed X inactivation has been found.

The evolution of the lesions in females can be in- terpreted as representing death of cells that have the mutant-bearing X chromosome as the active one and

their replacement by cells in which the normal X chromosome is active. This leads to extremely skewed X inactivation patterns in females, which save them from the lethal effect of the mutation. Other interpre- tations suggest a vasculopathy as the major patho- genetic mechanism for ophthalmological and brain damage.

Chapter 56 Incontinentia Pigmenti 414

Fig. 56.2. Follow-up MRI of the girl shown in Fig. 56.1. She is now 5 months old.There is a serious cystic degeneration of the deep and subcortical cerebral white matter, more prominent- ly on the left than on the right. The overlying cortex is also

involved. Courtesy of Dr. N. Wolf, Department of Pediatric Neu- rology, and Dr. A Seitz, Department of Neuroradiology, Univer- sity Hospital Heidelberg, Germany

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56.4 Therapy

No specific treatment is available.

56.5 Magnetic Resonance Imaging

In IP, the MRI findings are highly variable. In neonates with signs of active encephalopathy, MRI shows variably extensive areas of hemorrhagic cortex and white matter necrosis and edema suggestive of encephalitis, in particular herpes encephalitis (Fig. 56.1). Cystic degeneration may follow (Fig. 56.2).

In some patients the lesions are small, whereas in oth- er patients the abnormalities involve most of one or both cerebral hemispheres. In the chronic stage, signs

of gliotic scar tissue, focal atrophy, and secondary cortical dysplasia in the form of ulegyria are common (Fig. 56.3). The scar tissue may be unilateral or bilat- eral, symmetrical or asymmetrical. The lesions usual- ly involve both cortex and white matter of the cerebral hemispheres, but the most severe lesions are usually seen in the deep white matter. The lesions may also be similar to those seen in periventricular leukomalacia with mild, symmetrical or asymmetrical dilatation of the lateral ventricles due to loss of white matter vol- ume, periventricular white matter signal abnormali- ties, and disfiguration of the lateral ventricles due to the gliotic scarring (Fig. 56.3). The corpus callosum is thin. Lesions may also be seen in the cerebellum. De- velopmental cerebral anomalies may also be present, including polymicrogyria and neuronal heterotopias.

56.5 Magnetic Resonance Imaging 415

Fig. 56.3. A 13-month-old girl with IP. Note the extensive damage to the white matter of the right cerebral hemisphere.

The white matter damage on the left is much milder.The lateral ventricles are dilated, more so on the right than on the left.

There is retraction of the cortex on the right, which is folded with deep narrow sulci (ulegyria). Courtesy of Dr. W.J. Feikema, Department of Neurology, Deventer Ziekenhuis, Deventer,The Netherlands