A 6-day-old girl is brought by her parents to the emergency department for a rash on her arms and chest. The parents noted that over the past 3 days, the baby has had intermittent episodes of right eye deviation and upper extremity stiffening. These episodes lasted approximately 30 seconds, occurred approximately 3 times per day and were associated with cyanosis. The family history was notable for seizures in a maternal aunt. On physical examination the infant was quiet, seemingly withdrawn with stable vital signs. The infant had erythematous papules and vesicles, some of which had eroded with crusting on the arms and anterior chest (Figure 228-1). A direct fluorescent antibody test and culture from the lesions were negative for herpes simplex virus. Skin biopsy of the lesions showed spongiotic dermatitis with many eosinophils and large dyskeratotic cells. Based on the skin lesions and the neurological manifestations, the infant was diagnosed with incontinentia pigmenti. Genetic, neurologic, and ophthalmology consults were obtained.

• 
  

  Incontinentia pigmenti (IP) is an X-linked dominant systemic disease, usually lethal in males, and characterized by skin involvement at birth in 50 percent of cases. IP is a rare genodermatosis that presents in the neonatal period.

  
  
• 
  

  The disease involves tissues of ectodermic and mesodermic origin including cutaneous tissue, teeth, eyes and the central nervous system (CNS), amongst other organs.¹

Bloch-Sulzberger syndrome.

• 
  

  The incidence of IP is 1 case per 40,000.¹ It is more common in Caucasians than other ethnicities.

  
  
• 
  

  Because IP is an X-linked dominant disease, affected male fetuses usually do not survive, and therefore over 97 percent of living affected individuals are female.

  
  
• 
  

  IP has high penetrance. Most persons with IP begin to express the phenotype within a few months of birth.²

• 
  

  This X-linked dominant disorder is caused by mutations in the gene known as NEMO (NF-kappa essential modulator, also known as IKK-gamma). The gene NEMO encodes a protein that regulates the function of various chemokines, cytokines, and adhesion molecules, and is essential for protection against tumor necrosis factor induced apoptosis, inflammatory, and immune response³.

  
  
• 
  

  With this mutated gene, endothelial cells and other cells throughout the body can overexpress chemotactic factors specific for eosinophils, explaining why serum eosinophilia is common in IP patients.

  
  
• 
  

  The epidermal skin lesions also show extensive involvement of eosinophils. It appears that the eosinophils, combined with other factors, lead to extensive inflammation, affecting not only the skin, but also endothelial cells.

  
  
• 
  

  It is believed that this inflammation leads to vaso-occlusion, which results in ischemia, causing both the retinal and neurologic manifestations of IP.

• 
  

  Family history appears to be the only known risk factor for IP.

  
  
• 
  

  Living males are likely to be affected with Klinefelter syndrome, where an extra X chromosome is present (XXY).

Clinical Features

• 
  

  Skin manifestations are prominent and develop in four stages:⁴

  
  
  
  
  • 
    

    Stage 1—Erythematous papules and vesicles (Bullous stage) that appear in crops in linear streaks along the lines of Blaschko (lines along which skin and appendages, such as hair, melanocytes, and eccrine glands migrate during embryogenesis; Figures 228-2 to 228-4). Presentation is usually at birth or within the neonatal period. Each crop typically lasts 1 to 2 weeks.

    
    
  • 
    

    Stage 2—“Verrucous stage” that consists of hyperkeratotic warty papules or plaques in linear or swirling patterns (Figures 228-1 and 228-2). This stage usually last weeks to months.

    
    
  • 
    

    Stage 3—Streaks of hyperpigmentation develop in a “marble cake” or swirled pattern typically occuring at 3 to 6 months of age, often begins to fade in adolescents, but can persist into adulthood (Figure 228-5).

    
    
  • 
    

    Stage 4—By the second or third decade of life, the hyperpigmented streaks become hypopigmented and atrophic.

  
  
• 
  

  All stages may be present simultaneously, and may also occur in utero. Additional cutaneous changes include patchy alopecia, woolly-hair nevus, and nail dystrophy.

  
  
• 
  

  Systemic abnormalities occur in nearly 80 percent of patients and include:

  
  
  
  
  • 
    

    Dental abnormalities (i.e., adontia or conical deformities of the teeth).

    
    
  • 
    

    Ocular problems (strabismus, cataracts, and retinal vascular changes leading to blindness).

    
    
  • 
    

    Neurologic abnormalities (seizures, intellectual disability, mental retardation, and spastic paralysis).

    
    
  • 
    

    Structural malformations (less frequently).

  
  
• 
  

  In 1993, Landy and Donnai proposed a set of clinical diagnostic criteria for IP.⁵ The criteria focus on whether or not the suspected patient has a first-degree relative with IP. If this relative exists, then only one of the following is needed for diagnosis of IP:

  
  
  
  
  • 
    

    History or evidence of typical skin lesions.

    
    
  • 
    

    Pale, hairless, atrophic linear skin streaks.

    
    
  • 
    

    Dental anomalies.

    
    
  • 
    

    Retinal disease.

    
    
  • 
    

    Multiple male miscarriages.

  
  
• 
  

  If a first-degree relative with IP cannot be established, then diagnostic criteria are separated into major and minor categories.

  
  
  
  
  • 
    

    Major criteria—Skin lesions that occur in stages from infancy to adulthood.

    
    
    
    
    • 
      

      Erythematous lesions followed by vesicles anywhere on the body (sparing the face), usually in a linear distribution.

      
      
    • 
      

      Hyperpigmented streaks and whorls respecting Blaschko lines, occurring mainly on the trunk and sparing the face, fading in adolescence.

      
      
    • 
      

      Pale, hairless, atrophic linear streaks or patches.

    
    
  • 
    

    Minor criteria:

    
    
    
    
    • 
      

      Hypodontia or anodontia (partial or complete absence of teeth), microdontia (small teeth), or abnormally shaped teeth.

      
      
    • 
      

      Alopecia, wiry coarse hair.

      
      
    • 
      

      Mild nail ridging or pitting, hypertrophied, or curved nails.

      
      
    • 
      

      Retinal abnormalities.

  
  
• 
  

  If a first-degree relative with IP cannot be established, one major criteria and two or more minor criteria are needed for diagnosis. If none of the minor criteria are present, then a diagnosis other than IP should be considered.