Incontinentia Pigmenti

Incontinentia pigmenti is an X-linked dominant genodermatosis with skin lesions in four stages along the lines of Blaschko, with abnormalities of the eyes, teeth, hair, nails and central nervous system.

It is rare (about 1 in 40,000 births), mostly in girls. Most male foetuses with the variant do not survive. Survival in boys is possible with Klinefelter syndrome (47,XXY) or somatic mosaicism.

Variants in IKBKG (NEMO), most often a recurrent deletion of exons 4 to 10 (about 80%), cause it. About 65% of cases are new variants, and in other families the mother carries the variant.

Pathophysiology.

Loss of NEMO prevents activation of NF-kappa B, so cells are more sensitive to apoptosis and inflammation. Random X inactivation leaves a mosaic of normal and abnormal cells.

Eosinophil attracting chemokines produce the inflammatory first stage, and the cells with the variant are later eliminated by selection.

• Stage 1 (birth to 4 months): linear vesicles and bullae on the limbs and trunk, with blood eosinophilia.
• Stage 2 (weeks to months): warty, hyperkeratotic linear plaques.
• Stage 3 (from about 6 months into adulthood): swirled, slate grey or brown hyperpigmentation along Blaschko lines, fading in adulthood.
• Stage 4: pale, hairless, atrophic streaks on the limbs, often in adulthood.
• Hypodontia or conical teeth, scarring alopecia, nail dystrophy, retinal vascular disease, seizures, spastic paresis and intellectual disability.

Red flags.

• Retinal vascular changes in infancy, which can lead to detachment and blindness.
• Seizures or encephalopathy, or stroke like illness in the first months.

• Clinical diagnosis from the stages of the skin lesions, with major and minor criteria. Eosinophilia in stage 1 supports the diagnosis.
• Genetic testing for IKBKG (including the common deletion). Skin biopsy shows eosinophilic spongiosis (stage 1) and pigment incontinence (stage 3) if the diagnosis is uncertain.
• Eye examination with retinal imaging at diagnosis, brain MRI for neurological signs or when the retina is abnormal, and dental review.

Differential diagnosis.

• Bullous impetigo, herpes simplex infection and epidermolysis bullosa in infants (stage 1).
• Linear and whorled naevoid hypermelanosis, epidermal naevus and hypomelanosis of Ito.
• Mastocytosis and linear lichen planus.

• Skin care in stage 1: avoid trauma, use non-adherent dressings, and treat infection. Topical corticosteroids may reduce inflammation in a few lesions. Later stages need no treatment.
• Ophthalmology every month for the first 3 months of life, then every 3 months until 1 year, every 6 months until 3 years, and yearly after. Laser photocoagulation or intravitreal anti-vascular endothelial growth factor treatment for retinal neovascularisation.
• Seizures: anticonvulsants. Brain MRI and early developmental support. Dental management of absent or malformed teeth (prostheses).
• Genetic counselling: a woman with the variant has a 50% risk of an affected daughter and a risk of miscarriage of male foetuses. Offer testing to mothers and relatives.

Special groups. Boys: usually have Klinefelter syndrome or mosaicism, and need genetic and endocrine review.

Monitoring. Eye, neurological and dental review at each visit, with yearly eye review in adulthood.

Referral and escalation. Paediatric ophthalmology (urgent in infants), neurology, genetics and dentistry.