Incontinentia pigmenti

1 - DEFINITION OF THE DISEASE, CLINICAL PICTURE, AND STAGE

Incontinentia pigmenti is a rare X-linked genodermatosis. It is a multisystem disorder that is characterised by involvement of the skin, teeth, eyes, and central nervous system. It is a type of ectodermal dysplasia related to abnormalities of the NF-kappaB pathway. It mainly affects girls and it is generally lethal in boys [1]. The typical phenotype is the result of functional mosaicism, a phenomenon that arises in X-linked dominant disorders due to the mechanism of random inactivation of one of the X chromosomes (lyonization). The affected areas correspond to the cells that express the X chromosome carrying the genetic abnormality. At birth patients present a linear erythematous and vesicular outbreak that progresses over time to become verrucous, hyperpigmented, and then atrophic [2].

The gene responsible is known as IKK-γ or NEMO. It codes for a protein named NEMO, which is a regulatory subunit of the I-Χβ-kinase (IKK) enzyme complex [3]. This complex plays a role in activating the transcription factor NF-kB, which controls the activity of a number of target genes that code for chemokines, cytokines, adhesion molecules, and molecules that protect against apoptosis. IP cells are highly susceptible to apoptosis induced by TNF, which suggests that this cytokine plays a role in the development of the cutaneous lesions and the ophthalmological and neurological abnormalities associated with IP. A preferential mutation in which there is significant genomic reorganisation involving deletion of exons 4 - 10 of the IKK-γ gene leading to loss of NEMO function is found in almost 85% of cases of IP, mainly in de novo forms of the disease.

1.1 - CUTANEOUS MANIFESTATIONS

Incontinentia pigmenti classically progresses through four successive stages. The duration of each stage varies from one individual to another and the different types of lesions can coexist. The cutaneous lesions usually follow Blaschko lines, which are the migration lines of embryonic skin cells.

Stage I – The bullous stage is characterised by vesicles on an erythematous and oedematous base following a linear pattern (Figure 1). The rash is usually absent at birth and appears in the first hours or days of life. This phase usually resolves before the age of 18 months, although rare later resurgences have been described, mainly during episodes of infection [4].

Stage II – The verrucous stage is characterised by replacement of the vesicles by hypertrophic verrucous lesions that continue to follow Blaschko lines (Figure 2). This stage generally resolves in a few months. In rare cases, stage II has been reported from birth after very swift regression of the vesicular lesions. Stage II can feature ungual dystrophy and abnormal eruption of dentition.

Stage III - The hyperpigmented stage, from which the disease derives its name, is characterised by brown or light grey hyperpigmentation that is whorl-shaped on the trunk and has a linear pattern on the limbs (Figure 3). Hyperpigmentation is not present at birth, developing between six months and one year, when stage II begins to regress. Hyperpigmentation fades in the second decade of life.

Stage IV - The atrophic stage is characterised by a hypopigmented appearance and alopecia following a linear pattern that is especially noticeable at the extremities of the scalp (Figure 4).

The cutaneous manifestation is associated with involvement of head and body hair. Areas of alopecia may be located on the scalp, the extremities, or the trunk. Alopecia of the scalp can correspond to an area of scarring after a stage I bullous outbreak or indeed it can be present from the outset (Figure 5). These areas of alopecia may be small and barely visible. Hair is often fine and sparse, and eyelashes and eyebrows may also be sparse.

1.2 - EXTRACUTANEOUS MANIFESTATIONS

The extracutaneous manifestations determine the prognosis.

Ophtalmological involvement

Ophthalmological involvement has an inflammatory and ischaemic basis. It initially affects the retina, and is characterised by defective development of the retinal vessels and the retinal pigment epithelium cells. Secondary retinal ischaemia entails neovascularisation followed by exudation and fibrosis. Patients with IP have an increased risk of retinal detachment, generally arising in childhood before the age of six [5, 6]. Other reported abnormalities include severe myopia, strabismus, optic atrophy, cataracts, and uveitis. Ophthalmological abnormalities are seen in around 20% of IP patients. It seems to be the case that the presence of ophthalmological abnormalities may be a marker for associated neurological involvement.

Neurological involvement

Neurological involvement also has an inflammatory and ischaemic basis, with accumulation of cerebral infarcts [7]. Neurological abnormalities in IP often develop early in life. They include seizures in the neonatal period, mental retardation, and other abnormalities such a motor deficits or spastic paralysis. A cerebral MRI may show abnormalities such as patches of necrosis, delayed myelination, and abnormalities of the corpus callosum. They are present in 15 - 30% of patients, depending on the study. Male patients with IP are more likely to present neurological complications.

Odontological manifestations

Dental signs in IP are present in almost 80% of patients and they are an important factor for diagnosis as they persist throughout life [2]. Typical signs include delayed eruption of dentition, oligodontia, crown malformation with conical teeth and talon cusps (Figure 6). Delayed eruption of teeth is a constant finding. There is generally no dysplasia of the enamel.

2 - LINKS

Genodermatoses & Rare Skin Disorders Network: Incontinenta Pigmenti

Incontinentia Pigmenti International Foundation