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Incontinentia pigmenti

Orpha number ORPHA464
Synonym(s) Bloch-Siemens syndrome
Bloch-Sulzberger syndrome
Prevalence 1-9 / 1 000 000
Inheritance
  • X-linked dominant
Age of onset Neonatal/infancy
ICD-10
  • Q82.3
OMIM
UMLS -
MeSH
  • D007184
MedDRA -
SNOMED CT
  • 367520004

Summary

Incontinentia pigmenti (IP) is a rare X-linked dominant multi-systemic ectodermal dysplasia usually lethal in males and presenting neonatally in females with a bullous rash along Blashko's lines (BL) followed by verrucous plaques evolving over time to hyperpigmented swirling patterns. It is further characterized by teeth abnormalities, alopecia, nail dystrophy and affects occasionally the retina and the central nervous system (CNS).

Birth prevalence is 1/ 142,857. The female to male ratio is 20:1.

IP cutaneous findings typically present perinatally with an erythematous vesicular rash (bullous stage I) following BL: linear on extremities, swirled on trunk and head. Stage I evolves within a few months to a verrucous stage II characterized by wart-like plaques, lasting weeks to months. Stage III hyperpigmentation along BL occurs most frequently on the trunk and limbs and begins within months and can persist to adulthood. These three stages are not sequential, as stage I rash can recur during febrile illness. Stage IV, presenting from adolescence onwards, has hypopigmented, hairless regions following BL mostly evident on the lower extremities. 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 with retinal neovascularization (RNV) conferring risk of retinal detachment and microphthalmia. CNS abnormalities may comprise microcephaly and neonatal stroke which can result in seizures, neurocognitive and motor impairments. The majority (>60%) of patients are neurologically normal.

IP is caused by familial (10-25%) or sporadic de novo (>50%) mutations of the NF-kappaB essential modulator gene IKBKG (formerly NEMO). A common exon 4-10 deletion underlies 80% of cases.

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).

Stage I may be misdiagnosed as bullous impetigo, epidermolysis bullosa (see these terms), herpes or varicella. Differential diagnosis of stage II includes warts, molluscum contagiosum, and epidermal nevus syndrome (see this term). Any condition with 'linear and swirled' pigmentation overlaps with stage III. Stage IV resembles scarring, vitiligo, Ito hypomelanosis (see these terms), or other hypopigmentations with localized alopecia. Additional reported differential diagnoses are Naegeli-Franceschetti-Jadassohn syndrome and Norrie's disease (see these terms).

Fertility is normal except for the miscarriage of affected males. Genetic prenatal diagnosis is available.

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.

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. Appropriate specialists are required for RNV monitoring and treatment (cryotherapy and laser photocoagulation) and regular procedures should be followed if retinal detachment occurs. Neurological involvement necessitates a pediatric neurologist, whereas developmental screening and additional complementary therapy may be recommended in cases with developmental delay.

Life expectancy is normal. Those without neonatal CNS abnormalities typically have normal physical and cognitive development.

Expert reviewer(s)

  • Dr Angela SCHEUERLE

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Detailed information

Guidance for genetic testing
  • EN (2013,pdf)
Clinical genetics review
  • EN (2010)
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