Incontinentia pigmenti (ORPHA:464)
An X-linked syndromic muti-systemic ectodermal dysplasia presenting neonatally in females with a bullous rash along Blaschko's lines (BL) followed by verrucous plaques and hyperpigmented swirling patterns. It is further characterized by teeth abnormalities, alopecia, nail dystrophy and can affect the retinal and the central nervous system (CNS) microvasculature. It may have other aspects of ectodermal dysplasia such as sweat gland abnormalities. Germline pathogenic variants in males result in embryonic lethality.
Epidemiology
The birth prevalence is approximately 1/ 143,000. The female to male ratio is 20:1.
Clinical description
The disorder cutaneous findings typically present perinatally with an erythematous vesicular rash (bullous stage I) following BL: linear on extremities, swirled on trunk and head. Classically, Stage I evolves to a verrucous stage II characterized by wart-like plaques then to Stage III hyperpigmentation along BL that can persist to adulthood. This evolution varies and some adults report persistence of Stages I and II, usually with febrile illness, well into adulthood. These three stages are not sequential, as stage I rash can recur during febrile illness. The so-called Stage IV findings have hypopigmented, hairless regions following BL mostly evident on the lower extremities; however, it is possible that these areas of skin dysplasia may be present from an earlier age, but not visible until the growth of adult body hair. About 50% of IP symptoms are extracutaneous. Delayed dentition, missing, and/or malformed cone shaped teeth occur in most cases. Other manifestations include onycodystrophy, alopecia and a wide range of ophthalmologic abnormalities from primary microphthalmia, to reactive retinal neovascularization (RNV) conferring risk of retinal detachment. CNS abnormalities may comprise microcephaly and neonatal stroke that can result in seizures, neurocognitive and motor impairments. The majority (>60%) of patients are neurologically normal.
Etiology
IP is caused by familial (10-25%) or sporadic de novo (>50%) mutations of the NF-kappaB essential modulator gene IKBKG (formerly NEMO). In females, a common exon 4-10 deletion underlies 65% of cases, 8.6% have a sequence variant, and about 4% have a gene deletion.
Diagnostic methods
Typical skin lesions and genetic testing are sufficient for diagnosis. Leukocytosis and eosinophilia may be noted. Skin histology shows eosinophilic spongisostic bulles (stage I); hyperkeratotic and acanthotic epidermis with dyskeratotic keratinocytes (stage II) and loose dermal melanine deposits (stage III).
Differential diagnosis
Stage I may be misdiagnosed as bullous impetigo, inherited epidermolysis bullosa, herpes, or varicella. Differential diagnosis of stage II includes warts, molluscum contagiosum, and epidermal nevus syndrome. Any condition with 'linear and swirled' pigmentation overlaps with stage III. Stage IV resembles scarring, vitiligo, or other hypopigmentations with localized alopecia. Note that chromosomal mosaicism can manifest swirled and linear pigmentation abnormalities in both males and females. Additional reported differential diagnoses are Naegeli-Franceschetti-Jadassohn syndrome and Norrie's disease.
Antenatal diagnosis
Fertility is normal except for the miscarriage of affected males. Genetic prenatal diagnosis is available.
Genetic counseling
IP is inherited X-linked dominantly. An affected woman has a 50% risk of having affected children. Live-born affected males should be checked for a 47,XXY karyotype.
Management and treatment
Treatment is symptomatic, including standard management of blisters (not opening them and avoidance of trauma), topical treatment (medication, oatmeal baths) and addressing infections (as in cellulitis). Dental abnormalities should be managed by a pedodontist in combination with speech therapy and a pediatric nutritional program as needed. Appropriate specialists are required for RNV monitoring and treatment (cryotherapy and laser photocoagulation) and regular procedures should be followed if retinal detachment occurs. Early retinal angiograms may be indicated. Neurological involvement necessitates a pediatric neurologist, whereas developmental screening and additional complementary therapy may be recommended in cases with developmental delay.
Prognosis
Life expectancy is normal. Those without neonatal CNS abnormalities typically have normal physical and cognitive development.

                            Last update: 
                            November 2019


                            - Expert reviewer(s): 
                            Dr Angela SCHEUERLE