Introduction

• Definition: Rare X-linked genetic disorder affecting the skin, hair, teeth, nails, eyes, and CNS.
• Prevalence:
  • Reported prevalence: ~1.2/100,000 in Europe.
  • Female:Male ratio: 20:1.
  • High penetrance with variable expressivity.
• Demographics: Primarily affects females; rare in males (due to male lethality).

Clinical Characteristics

1. Skin Lesions:

   • Follow Blaschko lines (cell migration pathways during embryogenesis).
   • Evolve through four stages:
     1. Stage I (Bullous):
        • Blister-like eruptions (linear on extremities, circumferential on the trunk).
        • Onset: Birth to ~8 weeks; resolves by ~18 months.
     2. Stage II (Verrucous):
        • Wart-like rash, linear or circumferential.
        • Onset: Resolves stage I; lasts months to years.
        • May include dystrophic nails and delayed tooth eruption.
     3. Stage III (Hyperpigmentation):
        • Slate gray/brown swirled patterns.
        • Onset: ~6 months; persists into adulthood, fades in late teens/20s.
     4. Stage IV (Atretic):
        • Linear hypopigmentation, alopecia (scalp, trunk, extremities).
        • Follows fading hyperpigmentation; not present in all individuals.

2. Hair:

   • Alopecia (patchy or generalized).
   • Sparse, wiry, or lusterless hair.
   • Sparse eyelashes or eyebrows.

3. Teeth:

   • Common abnormalities:
     • Hypodontia, microdontia, conical shapes, delayed eruption.
     • Enamel is normal; anomalies vary widely.

4. Nails:

   • Dystrophic nails: lined, pitted, or brittle (resembling fungal infections).
   • Most common during stage II; transient or chronic.

5. Ophthalmologic:

   • Retinal hypervascularization (20%-77% risk):
     • Leads to retinal detachment if untreated.
     • Risk highest in infancy and childhood.
   • Other findings:
     • Strabismus, cataracts, optic atrophy, retinal pigmentary changes, microphthalmia.

6. Central Nervous System (CNS):

   • Reported in ~30% of cases:
     • Seizures (most within the first year; focal clonic type most common).
     • Neurovascular abnormalities (vasculopathy-related strokes or ischemia).
     • Intellectual disability: Variable, more common in simplex cases.
   • Imaging findings:
     • Periventricular leukomalacia, delayed myelination, cystic changes, and ventricular dilation.

7. Other:

   • Breast anomalies: Aplasia or supernumerary nipples.
   • Leukocytosis with eosinophilia during stages I/II.
   • Rare complications: Pulmonary hypertension.

Genetics

• Gene: IKBKG (Xq28).
• Pathogenic Variants:
  • Most common: 11.7-kb deletion in IKBKG.
  • Variant types include missense, frameshift, nonsense.
• Inheritance:
  • X-linked dominant.
  • Female carriers: 50% risk of transmitting pathogenic variants.
  • Male lethality: Rarely survive due to somatic mosaicism or 47,XXY karyotype.

Diagnosis

1. Clinical Diagnosis:
   • Presence of one major criterion (e.g., skin lesions in characteristic stages).
   • Minor criteria: Dental, hair, nail, or eye abnormalities; family history.
2. Genetic Testing:
   • Targeted molecular testing for IKBKG.
   • Skin biopsy (rarely needed) for eosinophilic infiltration or melanin granules.
3. Imaging:
   • Brain MRI for CNS abnormalities.
   • Ophthalmoscopy for retinal changes.

Management

1. Treatment:
   • Skin: Standard care for blisters and infections.
   • Dental: Pedodontic care, dental implants, or prosthetics.
   • Eye: Cryotherapy/laser therapy for neovascularization; surgery for detachment.
   • Neurology: Anti-seizure medications, developmental therapy, and education programs.
2. Surveillance:
   • Regular ophthalmologic exams (monthly in infancy; annually after 3 years).
   • Periodic neurologic assessments.
   • Dental evaluations.
3. Prevention:
   • Early intervention for skin infections and vision loss.
   • Address CNS complications proactively.

Genotype-Phenotype Correlations

• Variants in exon 10: Milder phenotype in females, fewer miscarriages.
• Variants associated with HED-ID: Males exhibit immunodeficiency but may also show IP features.

Prognosis

• Life expectancy is normal in the absence of significant neonatal complications.
• Fertility is unaffected, though there is an increased risk of miscarriages due to male lethality

Differential Diagnosis

1. Skin Manifestations by Stage:

   • Stage I – Bullous Stage:
     • Differential: Congenital herpes simplex, varicella, staphylococcal/streptococcal bullous impetigo, epidermolysis bullosa.
     • Diagnostic tests:
       • Infectious diseases: Lesion scrapings and cultures.
       • Epidermolysis bullosa: Skin biopsy, immunofluorescent mapping, or genetic testing.
   • Stage II – Verrucous Stage:
     • Differential: Warts or molluscum contagiosum.
     • Notes: Patterned lesions in Blaschko lines are more likely IP.
   • Stage III – Hyperpigmentation Stage:
     • Differential: Mosaic chromosome abnormalities (e.g., hypomelanosis of Ito), linear pigmentation conditions.
     • Diagnostic approach:
       • Chromosomal karyotyping (blood/skin samples).
       • Hypomelanosis of Ito: Hypopigmented areas abnormal (opposite of IP).
   • Stage IV – Atretic Stage:
     • Differential: Scarring conditions, vitiligo, piebaldism.
     • Notes: Medical history distinguishes IP (preceding stages) from other conditions.

2. Other Manifestations:

   • Retinal Neovascularization:
     • Differential: Retinopathy of prematurity, familial exudative vitreoretinopathy, Norrie disease.
   • CNS Abnormalities:
     • Differential: Conditions with congenital brain anomalies (e.g., polymicrogyria, heterotopias).
   • Nail and Hair Findings:
     • Differential: Other ectodermal dysplasias.

3. Genetic Conditions:

   • Naegeli syndrome: Resembles IP but includes hyperhidrosis and keratosis. Does not evolve in stages.
   • Autosomal dominant piebaldism: Limited to skin and does not progress.

Management

Evaluations Following Diagnosis:

1. Initial Assessments:

   • Full physical exam: Focus on skin, hair, nails, teeth, and neurologic status.
   • Ophthalmologic evaluation for retinal changes.
   • Neurologic evaluation (EEG, MRI, or MRA if indicated).
   • Developmental and cardiology assessments if delays or pulmonary hypertension are present.

2. Multidisciplinary Team:

   • Clinical geneticist or genetic counselor.
   • Pediatric dermatologist, neurologist, ophthalmologist, pedodontist, speech pathologist, nutritionist.

Treatment of Manifestations:

1. Skin:
   • Standard care for blisters (avoid rupture, keep clean).
   • Topical treatments (e.g., oatmeal baths) for discomfort.
   • Monitor for secondary infections.
2. Dental:
   • Early referral to a pedodontist at six months or tooth eruption.
   • Dental implants as early as seven years.
3. Neurologic:
   • Seizures: Standard antiepileptic treatments.
   • CNS abnormalities: Functional therapy, spasticity management.
   • Developmental delays: Tailored educational programs.
4. Ophthalmologic:
   • Cryotherapy/laser photocoagulation for retinal neovascularization.
   • Standard care for retinal detachment.
5. Pulmonary Hypertension:
   • Neonatal management with standard protocols.

Prevention of Secondary Complications:

1. Skin:
   • Prevent infection by avoiding trauma to blisters.
   • Regular monitoring for inflammation or systemic involvement.
2. Eye:
   • Monitor for retinal detachment; prompt evaluation of vision changes or trauma.
3. Head Trauma:
   • Comprehensive eye exams in cases of head injury.

Surveillance:

1. Eye Examinations:
   • Monthly: Birth to 4 months.
   • Every 3 months: 4 months to 1 year.
   • Every 6 months: 1-3 years.
   • Annually: After 3 years.
2. Neurologic Assessments:
   • Routine evaluations by pediatrician, neurologist, or developmental specialist.
3. Dental:
   • Regular pedodontist or dentist visits.

Evaluation of At-Risk Relatives:

1. Testing:
   • Molecular genetic testing if familial pathogenic variant is known.
   • Comprehensive physical examination if variant is unknown.
2. Routine Eye Exams:
   • Early identification of retinal changes for at-risk individuals.

Pregnancy Management:

• General: Normal prenatal care unless complications arise.
• Retinal Issues: Avoid labor in affected mothers to reduce detachment risk.
• Miscarriage Risk: Higher than average due to male lethality.
• Prenatal Testing:
  • Determine fetal karyotype for counseling.
  • Discuss implications of 46,XX (IP), 46,XY (miscarriage risk), and 47,XXY (Klinefelter syndrome with IP).

Key Genetic Counseling Points

1. Inheritance Pattern: X-linked dominant.
2. Risk to Offspring:
   • Female carriers: 50% transmission risk; 33% affected females, 33% unaffected males, 33% unaffected females at birth.
   • Male lethality: Most male conceptuses with IKBKG loss-of-function variants miscarry.
3. Testing:
   • Offer preimplantation genetic testing.
   • Bank DNA for unidentified pathogenic mechanisms.