Incontinentia Pigmenti

Key Points at a Glance

Highlights of this disease

• Incontinentia pigmenti is an X-linked dominant genetic disorder caused by mutations in the IKBKG gene, with 97–98% of patients being female.
• Skin lesions evolve through four stages and show a characteristic distribution along Blaschko lines.
• Ocular complications occur in 35–77% of patients, with retinal neovascularization, avascular areas, and retinal detachment being the main findings.
• Retinal findings are often bilateral and relatively symmetric; wide-field fluorescein angiography (FA) is useful for early detection.
• Laser photocoagulation (PRP) is the standard treatment for retinal neovascularization, and progression to retinal detachment in treated eyes has been reported to be zero.
• Extracutaneous complications involve the central nervous system (30–50%), teeth (most common), and hair, in addition to the eyes.
• Regular ophthalmologic screening from an early age is essential for improving visual prognosis.

1. What is Incontinentia Pigmenti?

Incontinentia pigmenti (IP), also known as Bloch–Sulzberger syndrome, is an X-linked dominant genetic disorder. Mutations in the IKBKG gene (Xq28) impair the NF-κB pathway, leading to lesions in multiple organs including the skin, eyes, central nervous system, teeth, and hair.

The prevalence is reported as 1 in 50,000 births ²⁾ or approximately 1 in 40,000 newborns ⁴⁾, with an incidence of 0.7–1.2 per 100,000 births ⁵⁾. 97–98% of patients are female ⁵⁾, and males are usually homozygous for the X-linked dominant mutation, resulting in intrauterine death. Surviving male patients often have mosaicism ¹⁾. The estimated annual number of new cases worldwide is about 27.6 ²⁾.

25–35% of cases are familial, while the remainder are sporadic due to de novo mutations ²⁾. Extracutaneous manifestations occur in 70–80% of all patients ⁴⁾, with ocular complications in about 40% (56% on detailed evaluation using wide-field FA) ^{1, 4)}, central nervous system complications in 30–50% ⁴⁾, and dental abnormalities being the most common complication ⁴⁾.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Symptoms change gradually from infancy to adulthood.

• Skin blisters/rash: The first symptom, starting immediately after birth.
• Strabismus: Present in 18–33% of patients and may be a sign of ocular complications ⁵⁾.
• Vision loss: Occurs with progression of retinal lesions or retinal detachment (RD).
• Seizures/developmental issues: Due to central nervous system complications.
• Dental abnormalities: Morphological abnormalities, missing teeth, etc.
• Hair loss/nail deformities: Complications affecting hair and nails.

Clinical Findings

Skin Lesions (4 Stages)

Skin lesions are distributed along Blaschko’s lines (the migration pathways of skin cells during embryonic development). The four stages may overlap ²⁾.

Stage 1: Vesicular Stage

Timing: Begins at birth or within the first 2 weeks of life, and may persist up to 18 months ⁴⁾

Findings: Vesicular rash appears on the limbs and trunk.

Histology: Eosinophil infiltration (30–60%) with ²⁾

Stage 2: Verrucous stage

Timing: A few weeks to months after birth

Findings: Wart-like (verrucous) lesions form at the blister sites.

Stage 3: Hyperpigmentation stage

Timing: Infancy to school age

Findings: Characteristic whorled and linear hyperpigmentation. Occurs in 98% of patients²⁾.

Stage 4: Hypopigmentation stage

Timing: Adolescence to adulthood

Findings: Hyperpigmented areas become depigmented and atrophic. Some persist into adulthood.

Frequency of ocular complications and overall complication profile

The frequency of complications in each organ is shown below.

Affected site	Frequency
Skin (4 stages)	Almost all cases
Dental (dysplasia)	Most common complication4)
Ocular	36–77%5)
Central nervous system	28–66%5)

Details of ocular findings

Ophthalmic evaluation reveals retinal findings in 56% of patients¹⁾.

• Retinal neovascularization (RN): Occurs on a background of peripheral avascular zones. Spontaneous regression has been reported, with cases regressing at 116 and 140 days⁵⁾.
• Peripheral retinal avascular zones: The most important finding detected by wide-field FA.
• Fibrovascular proliferation and tractional changes: Seen in advanced cases.
• Retinal detachment (RD): The most severe complication. In the Chinese series by Peng et al. (122 eyes), RD occurred in 27%¹⁾.
• Strabismus: Exotropia is frequently associated with eyes showing optic disc pallor¹⁾.
• Optic atrophy: Present in approximately 4% of patients⁵⁾.

Bilateral findings are relatively symmetric in 82% of patients¹⁾.

Q Do skin blisters and pigmentation resolve on their own?

A

Skin lesions progress through four stages. Stage 3 pigmentation tends to gradually fade during school age to adolescence. However, stage 4 depigmentation and atrophic changes often persist partially into adulthood. Extra-cutaneous complications (ocular, neurological, dental) do not resolve spontaneously and require specialized regular follow-up.

3. Causes and Risk Factors

Genetic Background

Incontinentia pigmenti is caused by mutations in the IKBKG gene (also called NEMO) located at Xq28. Deletion of exons 4–10 accounts for approximately 90% of all mutations ⁶⁾. The remaining cases are due to minor mutations such as point mutations or exon duplications.

Examples of novel mutations include c.832C>T (p.Gln278*, exon 6) and c.614_624dup (p.Val209Argfs*76, exon 5) ³⁾, and c.723_724insCAGG (p.A242QfsX15, exon 5) ⁶⁾.

The presence of an IKBKG pseudogene (IKBKGP1) complicates genetic testing ^{3, 6)}.

X-Chromosome Inactivation and Phenotypic Variability

Even with the same mutation, clinical presentations can vary greatly within families. Skewed X-chromosome inactivation (lyonization) is the main cause of phenotypic variability ³⁾. If a higher proportion of cells inactivate the mutant X chromosome, symptoms may be milder.

NF-κB Pathway Impairment

IKBKG (NEMO) is a component of the IKK complex (NEMO, IKKα, IKKβ) and is essential for NF-κB activation ⁶⁾. NEMO deficiency due to mutations leads to loss of NF-κB function and increased sensitivity to TNF-α-induced apoptosis ^{3, 6)}. This results in widespread tissue damage in the skin, nerves, and retina.

Risk Factors

• Family history: 25–35% of cases are familial ²⁾. If the mother is affected, each pregnancy carries a 33% risk of the daughter developing the condition.
• Sporadic cases are also common, so the condition can occur even without a family history.

About Genetic Counseling

If you have been diagnosed with incontinentia pigmenti, we recommend consulting a genetic specialist. Because it is X-linked dominant, it is important to understand the genetic risks before future pregnancies. Additionally, the mother and sisters of a female patient may be asymptomatic carriers.

Q Please explain the inheritance pattern of incontinentia pigmenti and its effects on males.

A

It is X-linked dominant inheritance. From an affected mother, each pregnancy has about a 33% risk of passing the gene to a daughter and about 33% to a son. Males are usually hemizygous and often die in utero, but can survive if there is mosaicism ^{1, 2)}. The female-to-male ratio is about 37:1, with a strong female predominance ⁴⁾.

4. Diagnosis and Testing Methods

Diagnostic Criteria

The criteria revised by Minic et al. (2014) from the Landy & Donnai criteria (1993) are used ⁵⁾. The allocation of major and minor criteria differs depending on whether the patient has a close relative with IP.

The presence of the typical four-stage skin lesions is central to the diagnosis.

Diagnostic Situation	Main Requirements
Family history present	Any one stage of typical skin lesions
No family history	Any one stage of typical skin lesions plus extracutaneous findings

Tests

• Genetic testing: GAP-PCR (detection of exon 4-10 deletions), MLPA (copy number changes), whole exome analysis ^{3, 6)}. Be aware of the influence of pseudogenes.
• Blood test: Eosinophilia (12–27%) is a characteristic finding⁵⁾.
• Skin biopsy: Confirms eosinophilic infiltration and melanin incontinence (melanin migration from epidermis to dermis)^{2, 6)}.
• Wide-field fluorescein angiography (FA): Essential for early detection of retinal avascular areas and neovascularization¹⁾. Can detect peripheral lesions often missed by routine fundus examination.
• Neurological evaluation: Brain MRI and developmental assessment. To check for central nervous system complications.
• Dental evaluation: Check for dental morphological abnormalities and missing teeth.

Differential Diagnosis

• Retinopathy of prematurity (ROP)
• Familial exudative vitreoretinopathy (FEVR)
• Eales disease
• Congenital herpes infection
• Neonatal pustulosis^{2, 3)}

Q What tests are used to diagnose incontinentia pigmenti?

A

Clinical diagnosis is based on the presence of typical skin lesions according to the revised Landy & Donnai criteria⁵⁾. For definitive diagnosis, IKBKG gene testing by GAP-PCR or MLPA is useful^{3, 6)}. Eosinophilia and skin biopsy findings are also used as adjuncts. For evaluation of ocular complications, fundus examination under anesthesia (EUA) and wide-field FA are important¹⁾.

5. Standard Treatment

There is no curative treatment; multidisciplinary management according to each complication is the standard.

Treatment for Skin

• Local care: Prevention of secondary infection during the blister stage is the top priority.
• Topical steroids: Used to reduce inflammation²⁾.
• Topical tacrolimus: Can be used for immunomodulation^{2, 3)}.
• No specific treatment for pigmentation or depigmentation has been established at this time.

Ophthalmic Treatment

Ophthalmic complications are directly linked to visual prognosis, so early detection and treatment are crucial.

Laser Photocoagulation (PRP)

Panretinal photocoagulation of the peripheral avascular retina is the standard treatment.

In a series of 18 patients (36 eyes) by Rai et al. (2024), 74% of treated eyes required only one laser session. None of the laser-treated eyes progressed to RD. Mean follow-up was 6.9 years¹⁾.

• Initial EUA (examination under anesthesia) + wide-field FA is performed, and laser is administered on the same day or early if necessary¹⁾.

Vitrectomy

If RD occurs, repair requires a combination of vitrectomy + scleral buckling + laser + silicone oil tamponade¹⁾.

Anti-VEGF Therapy

Off-label use is increasing, but comparative studies with laser are not yet available, and it is currently considered investigational¹⁾.

Ophthalmologic Screening Protocol

Regular ophthalmologic follow-up is key to visual prognosis.

• Recommended schedule (Holmstrom): Immediately after birth → monthly until 4 months of age → every 3 months until 1 year → every 6 months until 3 years → annually thereafter⁵⁾
• Rai et al. recommendation: Initial EUA + wide-angle FA → outpatient visit after 3–6 months → FA/EUA after 6–12 months → if stable, every 6 months + FA every 1–2 years¹⁾

Important Points in Ophthalmic Management

• Failure to perform regular screening may lead to progression of peripheral retinal neovascularization and risk of RD. One case reported a patient first seen in adolescence who developed RD without treatment¹⁾.
• Wide-angle FA in infants may require general anesthesia, so management at a well-equipped specialized ophthalmology facility is desirable.
• Although spontaneous regression of retinal neovascularization has been reported⁵⁾, delaying treatment in expectation of regression is not recommended.

Q How are ocular complications treated?

A

Laser photocoagulation (PRP) is the standard treatment for peripheral retinal avascular areas and neovascularization. In a report by Rai et al. (2024), 74% of treated eyes required only one laser session, and no progression to RD occurred in laser-treated eyes¹⁾. If RD develops, vitrectomy and scleral buckling are necessary¹⁾. Early screening and regular follow-up are the most important factors in preserving vision.

6. Pathophysiology and Detailed Mechanism

NF-κB Pathway and IKK Complex

Under normal conditions, the IKK complex (NEMO, IKKα, IKKβ) is activated by inflammatory cytokines such as TNF-α and IL-1⁶⁾. Activated IKK complex phosphorylates and degrades IκB, allowing NF-κB to translocate to the nucleus and express target genes. NF-κB plays a central role in inflammation, immune response, and protection against apoptosis³⁾.

When NEMO is deficient or dysfunctional due to IKBKG mutation, the IKK complex cannot form, and NF-κB activation is impaired. As a result, sensitivity to TNF-α-induced apoptosis is markedly increased, leading to damage to skin, nerve, and retinal cells^{3, 6)}.

Mechanism of Retinal Lesion Development

Abnormal inflammatory responses due to NEMO deficiency trigger the following cascade.

• Eotaxin overproduction → eosinophilia (30–60%) ²⁾ → tissue infiltration
• Eosinophil-derived proteolytic enzymes and reactive oxygen species → vascular endothelial damage
• Peripheral retinal vascular occlusion → ischemic avascular area formation
• Increased VEGF production → retinal neovascularization
• Fibrovascular proliferation of new vessels → tractional retinal detachment

X-chromosome inactivation and phenotypic diversity

In each cell, which of the two X chromosomes is inactivated is random. However, in IP, cells with the mutant X chromosome are often eliminated by apoptosis, and cells with the normal X chromosome survive preferentially (skewed X-chromosome inactivation). This ratio varies by tissue and individual, leading to a wide range of clinical presentations even with the same mutation ³⁾.

7. Latest research and future perspectives (investigational reports)

For patients: Please read carefully

The following content is currently under investigation or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Identification of novel IKBKG mutations and advances in genetic diagnosis

With the widespread use of next-generation sequencing, novel mutations that were previously missed are being identified. Chen et al. (2023) identified a nonsense mutation in exon 6 (c.832C>T) and a frameshift mutation in exon 5 (c.614_624dup) ³⁾, and Jiang et al. (2022) reported an insertion mutation in exon 5 (c.723_724insCAGG) ⁶⁾. The application of long-read sequencing is being considered to address the pseudogene (IKBKGP1).

Role of anti-VEGF therapy

Off-label use of anti-VEGF injections (bevacizumab, ranibizumab, etc.) is increasing ¹⁾. Direct comparative studies with laser are still lacking, and establishing efficacy and safety remains a challenge. Reports extrapolating findings from retinopathy of prematurity (ROP) to IP are accumulating.

Potential Applications of Propranolol

Propranolol (0.25–0.5 mg/kg every 6 hours), known to suppress the progression of ROP, is being discussed for its potential application to retinal neovascularization in IP ⁵⁾. Since IP and ROP share peripheral retinal ischemia as a common pathological basis, suppression of VEGF production by beta-blockers may have a therapeutic effect. Clinical evidence is currently limited.

Establishing Evidence for Wide-Field FA and Laser Treatment

The series by Rai et al. (2024) of 18 patients (36 eyes) provided relatively large-scale long-term ophthalmic follow-up data ¹⁾. The protocol of screening with EUA + wide-field FA followed by early laser intervention is showing efficacy. Future multicenter prospective studies are expected to establish a standard protocol.

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8. References

1. Rai RS, Li AS, Ferrone PJ. Ophthalmologic Presentations of Incontinentia Pigmenti. J VitreoRetinal Dis. 2024;8(2):186-191.
2. Vaghani UP, Qadree アカントアメーバ角膜炎, Mehta S, et al. Bloch-Sulzberger Syndrome: A Rare X-Linked Dominant Genetic Disorder in a Newborn. Cureus. 2023;15(11):e48823.
3. Chen H, Ji X, Lai Y, et al. Novel IKBKG gene mutations in incontinentia pigmenti: report of two cases. Front Med. 2023;10:1303590.
4. Katakam BK, Gurram NR, Chintagunta S, Dhabal A. Incontinentia Pigmenti: A Series of Six Cases with Isolated Cutaneous Involvement. Indian Dermatol Online J. 2024;15:259-262.
5. Dwiyana RF, Banjarnahor ID, Diana IA, et al. Retinal Neovascularization in Two Patients with Incontinentia Pigmenti. Clin Cosmet Investig Dermatol. 2022;15:803-808.
6. Jiang J, Zeng J, He Q, et al. NEMO Gene Mutations in Two Chinese Females with Incontinentia Pigmenti. Clin Cosmet Investig Dermatol. 2022;15:815-821.