Incontinentia pigmenti (IP) is a rare condition with X-linked dominant inheritance that affects the skin (▶ Fig. 16.1), eye, and central nervous system. It occurs primarily in females and infrequently in males. Female-to-male ratio is 20:1. Most of the affected males that survive show a somatic mosaicism for a 47,XXY karyotype. The estimated frequency of IP is 0.7 per 1,000,000 newborns. IP diagnosis is established in a proband with compatible clinical findings and a heterozygous mutation in IKBKG. Diagnostic criteria are listed in ▶ Table 16.1. At least one major criterion is needed to confirm IP. Minor criteria are usually seen in the presence of major criteria, and just support the diagnosis. Tooth abnormalities are the most frequent noncutaneous finding (approximately 80% of cases; ▶ Fig. 16.2 and ▶ Table 16.1).
Fig. 16.1 Incontinentia pigmenti. Swirling cutaneous hyperpigmentation.
(This image is provided courtesy of Ximena Fajre, MD.)
Fig. 16.2 Tooth anomalies in a patient with incontinentia pigmenti. Note peg-shaped tooth and other tooth anomalies. Note that top tooth are implants following reconstructive dental surgery.
bIncontinentia pigmenti skin alterations manifest in stages that evolve sequentially. The onset and duration of each stage is variable among patients, and not all affected individuals present with each stage. The skin anomalies can resolve to nonspecific minor abnormalities.
The phenotype is usually present in the first months of life. Penetrance is high, but expressivity is variable. For females without major systemic or neonatal complications, life expectancy is considered to be normal.
Central nervous anomalies are present in one-third of patients with IP and include seizures, intellectual disability, and, rarely, primary brain abnormalities such as agenesis of the corpus callosum, periventricular leukomalacia, cystic changes, myelination delays, ventricular dilatation, spastic paresis, occipital encephalocele, or polymicrogyria. Affected males are more likely to have neurologic anomalies. It is thought that central nervous system dysfunction is associated with microvasculature anomalies, resulting in ischemia. Neurovascular abnormalities are most frequently seen in the first year of life. There is evidence that in patients with neurological symptoms and multiple cerebral infarctions, corticosteroid therapy may be helpful.
Eosinophilia may be present, particularly in the first IP stages. Nevertheless, eosinophilia is not typically associated with any clinical manifestations and frequently resolves spontaneously. Eosinophilic infiltration may be helpful in confirming IP in a female patient with borderline clinical findings in whom molecular genetic testing has not identified a mutation.
Up of 75% of individuals have eye involvement, of which 60 to 90% have retinal findings. The most common is retinal peripheral nonperfusion (▶ Fig. 16.3), which may be complicated by retinal neovascularization, hemorrhage, and/or exudate. If peripheral ischemia is left untreated, retinal detachment may rapidly develop. Asymmetric retinal disease between eyes in the same individual and variable retinal findings within a family can occur. These differences can be explained by random X chromosome inactivation or epigenetic factors. One study found that the long-term follow-up risk of retinal detachment is approximately 22%, although they did not compare treated eyes to those without treatment. Significant risk factors are retinal neovascularization or ischemic optic neuropathy on initial examination. Most tractional detachments occur before the age of 3 years, whereas most rhegmatogenous detachments are seen in adults. Most retinal tears occur at the border of vascular and avascular retina. Sequelae also include optic atrophy and retinal pigmentary abnormalities.
Fig. 16.3 (a) Peripheral retinal fold in a patient with incontinentia pigmenti (right eye) (b) Left eye from the same patient is apparently normal, but angiography (c) reveals peripheral nonperfusion with abrupt vessel endings (arrows).
Patients with IP require multidisciplinary care including pediatric neurology, dentistry, developmental care, dermatology, and ophthalmology. All patients with IP retinopathy should be closely monitored throughout adulthood for the development of retinal complications. If initial intravenous fluorescein angiography (IVFA) in infancy is normal, then there is little, if any, long-term risk. Patients with peripheral retinal ischemia benefit from early ablation of the nonperfused retina by laser or cryotherapy. Retinal detachment can develop rapidly and therefore, especially if treatment is deferred, frequent follow-up is essential to identify early retinal traction, neovascularization, and hemorrhage.
16.2 Molecular Genetics
The IKBKG gene (Xq28) encodes nuclear factor-kappa B essential modulator (NEMO). When mutated, it predisposes cells to apoptosis from intrinsic factors. It is estimated that 65% of patients have a de novo mutation. The most common abnormality is an 11.7-kb deletion that affects exons 4 to 10. This is seen in 60 to 80% of affected females. Approximately 10% of parents of patients with IP carry two IKBKG benign variants, suggesting recombination as a possible pathologic mechanism that generates the 11.7-kb pathologic deletion. When IP occurs as the result of a de novo event, the paternal allele is more frequently affected. Exon 10 mutations are associated with milder IP manifestations in females and a lower risk of miscarriage.
There are two rare IKBKG allelic disorders that affect males exclusively. These are X-linked hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) and HED-ID with osteopetrosis and lymphedema. These two conditions are caused mostly by missense mutations in the gene. Another IKBKG-related phenotype is X-linked atypical mycobacteriosis (AMCBX1, OMIM 300636), a condition with immunodeficiency and susceptibility to both pyogenic bacteria and mycobacterial diseases.
16.3 Differential Diagnosis
As skeletal involvement, body asymmetry, severe neurologic deficits, severe alopecia, or hyperpigmentation that follows the lines of Blaschko are all uncommon findings in IP, these findings should raise consideration of other diagnoses. Nongenetic disorders with peripheral retinal nonperfusion include morning glory optic nerve, shaken baby syndrome, and retinopathy of prematurity (ROP). Although sickle cell disease may cause nonperfusion of the peripheral retina, it is extremely uncommon to do so in the first decade of life.
16.3.1 Herpes Simplex, Varicella, Bullous Impetigo, or Epidermolysis Bullosa
Herpes simplex, varicella, bullous impetigo, or epidermolysis bullosa should be considered in the differential diagnosis of stage 1 skin changes. These infectious diseases are associated with fever or inflammatory systemic symptoms. Scrapings and cultures of the lesions are diagnostic. Vesicles that appear after light trauma are distinctive of epidermolysis bullosa. IP diagnosis, besides molecular testing, is established by skin biopsy, electron microscopy, or immunofluorescence. These disorders do not have the peripheral retinal nonperfusion or dental abnormalities seen in IP and they are not familial.
16.3.2 Warts or molluscum contagiosum
These conditions may resemble stage 2 IP skin lesions but are not associated with dental or ophthalmic manifestations. Skin biopsy may be helpful.