Incontinentia Pigmenti

Clinical characteristics: Incontinentia pigmenti (IP) is a disorder that affects the skin, hair, teeth, nails, eyes, and central nervous system; it occurs primarily in females and on occasion in males. Characteristic skin lesions evolve through four stages:

1. I

   Blistering (birth to age ~4 months)

2. II

   Wart-like rash (for several months)

3. III

   Swirling macular hyperpigmentation (age ~6 months into adulthood)

4. IV

   Linear hypopigmentation

Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails are observed. Neovascularization of the retina, present in some individuals, predisposes to retinal detachment. Neurologic findings including seizures, intellectual disability, and developmental delays are occasionally seen.

Diagnosis/testing: The diagnosis of IP is established in a proband with at least one major criterion (characteristic skin lesion). Identification of a heterozygous IKBKG pathogenic variant in a female proband or a hemizygous IKBKG pathogenic variant in a male proband confirms the diagnosis if clinical features are inconclusive.

Management: Treatment of manifestations: Standard management of blisters and skin infections; dental care by a pedodontist; dental implants in childhood as needed; care by a speech pathologist and/or pediatric nutritionist if dental abnormalities interfere with chewing and/or speech; cryotherapy and laser photocoagulation of retinal neovascularization to reduce risk of retinal detachment; standard management of retinal detachment; referral to a pediatric neurologist for management of seizures, spasticity, or focal deficits; brain MRI for functional neurologic abnormalities and/or retinal neovascularization; developmental programs and special education as needed for developmental delay.

Prevention of secondary complications: Standard measures to reduce the risk of skin infection; evaluate for retinal detachment if vision decreases, strabismus appears, or head trauma occurs.

Surveillance: Eye examination: monthly until age four months, then every three months from age four months to one year, every six months from age one to three years, and annually after age three years. Assessment of neurologic function at routine visits with pediatrician, pediatric neurologist, or developmental pediatrician; routine evaluation by a pedodontist or dentist.

Evaluation of relatives at risk: Identification of affected relatives by physical examination and retinal examination so that screening ophthalmology examinations can be performed.

Genetic counseling: IP is inherited in an X-linked manner. About 65% of affected individuals have IP as a result of a de novo pathogenic variant. Heterozygous, affected women have a 50% chance of transmitting the IKBKG pathogenic variant at conception; however, male conceptuses with an IKBKG loss-of-function variant miscarry. Thus, the expected ratio among live-born children of a mother with IP is approximately 33% unaffected females, 33% affected females, and 33% unaffected males. To date, all males with IP have had either a 47,XXY karyotype or somatic mosaicism for the IKBKG pathogenic variant. A male with somatic and germline mosaicism may transmit the IKBKG pathogenic variant to daughters (females who inherit the pathogenic variant will be affected); an affected male would not transmit an IKBKG pathogenic variant to sons. Prenatal testing for pregnancies at increased risk and preimplantation genetic testing are possible if the familial pathogenic variant has been identified.