DISEASE CARD

Definition

Incontinentia Pigmenti (IP) is a rare X-linked dominant genodermatosis characterized by a swirling pattern of skin hyperpigmentation, and a broad spectrum of further clinical manifestation including abnormalities of the eyes, teeth, hair and central nervous system. It is almost exclusively seen in females, as the disease is usually lethal in hemizygous males. Bloch and Sulzberger first described the entire clinical features of the condition in 1928. The disease is caused by a mutation in the IKBKG (inhibitor of the kappa B kinase gamma) (previously NEMO) gene, which maps to Xq28.

Clinical Description

The most prominent clinical feature in IP is the characteristic cutaneous rash that shows 4 stages. The skin lesions themselves are rather benign and mainly cause cosmetic issues. The majority of individuals present at birth (or within the first six weeks of life) with an erythematous, inflammatory vesiculo-bullous (or pustulous) eruption. This rash is usually located on the extremities or scalp (sparing the face). During the second stage, which usually occurs after 2-6 weeks, the lesions change to verrucous, hyperpigmented papules. The third ‘hyperpigmented’ stage usually develops, when infants are between 12 and 26 weeks old and consists of the characteristic swirled or reticulate pattern of (macular) hyperpigmentation on the trunk and limbs. The final ‘atrophic’ stage is characterized by a pale scarring and hypopigmentation or hairless patches, but does not occur in all patients. The four stages may overlap and not necessarily follow the above mentioned order. Generally skin lesions tend to fade with time and are usually very subtle in adulthood.

Apart from the cutaneous feature, phenotypical expression varies greatly inter- and intrafamilial. Seventeen to 34 percent will experience problems with dentition. Anodontia/hypodontia can occur as well as delayed primary tooth eruption, abnormal “peg-shaped” appearance, microdontia and impacted teeth. Hair abnormalities (e.g. alopecia, hypertrichosis, wiry/coarse hair) are present in 28-38% of patients. Neurological abnormalities can be found in approximately 30% of patients and usually manifest before the 2nd year of life. They may include cerebral ischemia, cerebral dysgenesis or brain malformations (resulting in seizures, epilepsy), cerebral palsy and mental retardation. Eye defects are common, the most severe being vascular abnormalities of the retina and disorders of the retinal pigment epithelium, with the risk of irreversible loss of vision. Further symptoms include high-arched palate and supernumerary nipple. ^1-4

Pathogenesis

IP is an X-linked dominant disorder caused by a mutation in the IKBKG (previously NEMO - NF-kappa B Essential MOdulator) gene. More than half of the patients have a positive family history.⁵ Nearly all mutations cause frameshift and premature protein truncation, which are predicted to eliminate IKBKG function and cause cell lethality. Eighty percent of cases are due to a deletion spanning exons 4 to 10. It is thought that the evolution of the cutaneous eruptions is secondary to death of cells that have the mutant X chromosome, with replacement by cells with the normal X chromosome. Only a few percent of affected patients are males, who survive due to sex chromosome aneuploidies or somatic mosaicism.^6-8

Diagnosis

Diagnosis is usually made by assessment of the clinical features either at, or soon after birth. As most adults have very subtle skin findings, diagnosis is frequently missed. Mutation analysis of the IKBKG gene will supplement the clinical diagnosis and provide further supportive evidence to enable accurate genetic counselling. A skin biopsy that demonstrates intraepidermal spongiosis and vesiculation with eosinophilic inflammatory infiltrate, dyskeratotic keratinocytes and (melanin) pigmentary incontinence will support the diagnosis. Laboratory analysis in the neonatal period may show blood eosinophilia.

Diagnostic criteria

Major criteria:

• Typical IP skin changes distributed on the lines of Blaschko:

vesiculobullous stage | verrucous stage | hyperpigmented stage | atrophic/hypopigmented stage

Minor criteria

• Dental anomalies
• Ocular anomalies
• Central nervous system anomalies
• Alopecia
• Hair abnormalities
• Nail abnormalities
• Palate abnormalities
• Nipple and breast abnormalities
• Multiple male miscarriages
• Typical skin histopathologic findins

Additional conditions to confirm an IP Diagnosis

• No evidence of IP in a first-degree female relative: If no IKBKG mutation data available, require two or more major criteria OR one major and one minor criterion to confirm diagnosis

• Confirmed IKBKG mutation with any major or minor criterion confirms diagnosis

• Evidence of IP in a first degree female relative: requires one major criterion OR two minor criteria

• Eosinophilia and skewed X-chromosome inactivation support the diagnosis in all cases

Treatment

The various cutaneous manifestations in infancy generally resolve spontaneously. Areas of hyperpigmentation and atrophy will gradually improve and may disappear by the time the child reaches adulthood. Basic skin care and emollients may be beneficial for hyperkeratotic lesions or crusts.

Ophthalmological assessment in neonates is important due to the rapid progression of eye pathologies in the neonatal/early infancy period. Further, monitoring of visual complications is often necessary throughout the lifetime and treatment with laser photocoagulation or cryotherapy may become necessary in case of severe complications like retinal detachment and avascular retina.

Dental care and assessment is frequently needed as many may require successive dentures as a child with addition of dental implants and bridges later in adult life. Neurological pathologies / developmental disabilities will require assessment and management advices from a consultant neurologist.⁹

References

^{1. Minić S, Trpinac D, Obradović M. Systematic review of central nervous system anomalies in incontinentia pigmenti. Orphanet J Rare Dis. 2013;8:25.}

^{2. Minić S, Obradović M, Kovacević I, Trpinac D. Ocular anomalies in incontinentia pigmenti: literature review and meta-analysis. Srp Arh Celok Lek. 2010;138(7-8):408-413.}

^{3. Rosser T. Neurocutaneous Disorders. Continuum (Minneap Minn). 2018;2}

^{4(1, Child Neurology):96-129.}

^{4. Meuwissen ME, Mancini GM. Neurological findings in incontinentia pigmenti; a review. Eur J Med Genet. 2012;55(5):323-331.}

^{5. Carney RG. Incontinentia pigmenti. A world statistical analysis. Arch Dermatol. 1976;112(4):535-542.}

^{6. Fusco F, Bardaro T, Fimiani G, et al. Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappaB activation. Hum Mol Genet. 2004;13(16):1763-1773.}

^{7. Fusco F, Paciolla M, Conte MI, et al. Incontinentia pigmenti: report on data from 2000 to 2013. Orphanet J Rare Dis. 2014;9:93.}

^{8. Minić S, Trpinac D, Obradović M. Incontinentia pigmenti diagnostic criteria update. Clin Genet. 2014;85(6):536-542.}

^{9. Swinney CC, Han DP, Karth PA. Incontinentia Pigmenti: A Comprehensive Review and Update. Ophthalmic Surg Lasers Imaging Retina. 2015;46(6):650-657.}