What is the inheritance pattern of incontinentia pigmenti, also called Bloch-Sulzberger syndrome?

Autosomal dominant with full penetrance

How do the cardinal skin lesions of incontinentia pigmenti evolve?

Vesiculobullous lesions progressing to whorl-like pigmentary lesions over four stages The cardinal feature is progressive skin change, beginning as vesiculobullous lesions and passing through four stages to whorl-like pigmentary lesions.

Flat café-au-lait macules that darken steadily through puberty

Painless nodules that ulcerate then heal without pigment change

Diffuse ichthyotic scaling present unchanged from birth

In what proportion of patients with incontinentia pigmenti are eye findings seen?

About 35-40% Eye findings occur in 35-40% of patients with incontinentia pigmenti, so every suspected case needs a thorough eye examination.

The retinal findings of incontinentia pigmenti arise from which underlying process?

Retinal vascular occlusion Vascular occlusion underlies the retinal picture, producing avascularity, neovascularisation, haemorrhage, loss of the foveal pit and detachment.

Lysosomal storage within ganglion cells

Autoimmune photoreceptor destruction

Progressive choroidal neovascular ingrowth

Which ocular abnormality is the most commonly diagnosed eye finding in incontinentia pigmenti?

Retinal detachment Retinal detachment is the eye finding most often diagnosed in incontinentia pigmenti.

Retinal detachment in incontinentia pigmenti nearly always occurs within which age window?

The first six years of age Detachments nearly always occur within six years of age and are relatively rare in older patients.

How should the avascular peripheral retina of incontinentia pigmenti be treated?

Laser photocoagulation or cryotherapy, as in retinopathy of prematurity The avascular retina is treated much as in retinopathy of prematurity, with laser photocoagulation or cryotherapy of the avascular zone.

Immediate scleral buckle without laser

Topical corticosteroid drops alone

Observation until neovascularisation regresses

What is the current status of intravitreal anti-VEGF therapy in incontinentia pigmenti?

Investigated and promising, but not the standard of care Intravitreal anti-VEGF has been investigated and may prove promising, but it has not become the standard of care.

It is the established first-line treatment

Proven ineffective in randomised trials

Contraindicated because it induces tractional detachment

Which feature separates incontinentia pigmenti from retinopathy of prematurity, FEVR, sickle cell retinopathy and the Norrie spectrum?

The accompanying progressive skin lesions These conditions share the retinal picture, but none of them is associated with the skin findings of incontinentia pigmenti.

The presence of peripheral avascular retina

An enlarged foveal avascular zone

The occurrence of vitreous haemorrhage

Naegeli syndrome can resemble the skin lesions of incontinentia pigmenti. How does it differ?

It has no significant eye findings Naegeli syndrome affects skin and ectoderm and can look like the skin lesions of incontinentia pigmenti, but it does not produce significant eye findings.

It is confined to the oral mucosa

It causes bilateral optic nerve hypoplasia

It presents only after the fourth decade

Incontinentia pigmenti (IP): A full study

DISEASE

Incontinentia pigmenti (IP), also known as Bloch-Sulzberger syndrome, is a rare X-linked dominantly inherited syndrome manifesting at birth or early childhood.

The cardinal feature is the appearance of characteristic progressive skin lesions, first presenting as vesiculobullous lesions and then progressing to whorl-like pigmentary lesions over four stages.

IP also includes eye abnormalities, mostly occurring in the retina. The retinal findings stem from vascular occlusion and include neovascularization, hemorrhages, absence of the foveal pit, and exudative and tractional retinal detachments.

Pathologic changes in the central nervous system, teeth, and hair are also common in Incontinentia pigmenti (IP). Diagnosis is based on clinical systemic and ocular exams, as well as genetic testing.

There is no treatment for the disease as a whole; however, symptoms may be managed by medical or surgical intervention.

Ophthalmologic Exam and Findings

A thorough eye exam must be performed on those suspected of IP. Eye findings are seen in 35-40% of those with IP.

Both retinal and non-retinal findings are seen in Incontinentia pigmenti (IP). Retinal findings are common and include avascularity, neovascularization, hemorrhages, absence of a foveal pit, optic nerve atrophy, and exudative and retinal tractional detachments.

Retinal detachment is the most commonly diagnosed eye finding in IP. Due to the vaso-occlusive nature of IP, a cherry red foveal spot may be seen as choroidal perfusion and is not typically affected; however, observing the occlusive event in its acute stage is rare.

A blunted foveal pit and absence of normal parafoveal vascular pattern are also characteristic of IP, caused by vessel occlusion and subsequent vascular remodeling.

Occlusions of retinal vessels in the macula and the periphery are typically seen and are often accompanied by diffuse mottled hypopigmentation.

Retinal detachments, if present, nearly always occur within six years of age and are relatively rare in older patients. Additional non-retinal ocular manifestations include cataracts, uveitis, strabismus (18%), conjunctival pigmentation, optic atrophy (5%), and nystagmus. Phthisis bulbi can be the result of ocular Incontinentia pigmenti (IP).

An avascular peripheral retina is a significant feature of IP’s retinal manifestations. Typically, the neovascularization of the retina is more pronounced in the periphery, similar to retinopathy of prematurity.

Tufts of neovascularization can be found at the edges of the avascular retina. Fluorescein angiography is a critical study in the ophthalmic investigations for IP.

Often, enlargement of the foveal avascular zone is seen, which can be accompanied by large areas of avascularity anywhere in the retina.

Cortical blindness may sometimes be present due to vascular occlusions in the occipital cortex in IP. Neurologic consultation and MRI brain imaging should be obtained to investigate this possibility.

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Differential diagnosis

The differential diagnosis for the retinal manifestations of Incontinentia pigmenti (IP) include retinopathy of prematurity, familial exudative vitreoretinopathy, Eales retinopathy, sickle cell retinopathy, and the Norrie disease spectrum. However, skin findings are not associated with these conditions.

Incontinentia pigmenti

The differential diagnosis for the dermatologic findings in Incontinentia pigmenti (IP) is large and can be divided based on the stage of the skin lesions.

They include congenital herpetic infection, impetigo/epidermolysis bullosa, warts or molluscum contagiosum, hypomelanosis of Ito, scaring, and vitiligo.

Naegeli syndrome is a rare condition affecting the skin and ectoderm which can appear similar to the skin lesions of IP. It does not have significant eye findings.

Management

As IP has a genetic basis, there is no cure and treatment is limited to treating symptoms at this time.

General treatment

Because Incontinentia pigmenti (IP) is a multi-faceted condition, dermatologic, genetic, ophthalmic, neurologic, and dental consultations should be obtained.

Generally, brain imaging should be obtained (MRI) to investigate the occlusive consequences of IP in the brain. EEG should be obtained if seizures are present.

Developmental therapy may be needed. Skin lesions should be managed symptomatically to avoid infection or excessive scarring. Genetic therapies are not currently available for IP.

Ophthalmic treatment

The avascular retina should be treated similarly to retinopathy of prematurity with laser photocoagulation (or cryotherapy) of the avascular retina.

The occurrence of retinal detachments should be monitored with regular ophthalmological exams and surgical repair of detachments should be attempted by a vitreoretinal surgeon if appropriate. Vitrectomy with or without a scleral buckle is commonly performed.

Intravitreal anti-vascular endothelial growth factor has been investigated. While this may be a promising treatment, it has not become the standard of care.

REFERENCES

Buinauskiene J, Buinauskaite E, Valiukeviciene S. Incontinentia pigmenti (bloch-sulzberger syndrome) in neonates. Medicina (Kaunas). 2005;41(6):496-9.
Goldberg MF, Custis PH. Retinal and other manifestations of incontinentia pigmenti (bloch-sulzberger syndrome). Ophthalmology. 1993 Nov;100(11):1645-54.
Nelson DL. NEMO, NFkappaB signaling, and incontinentia pigmenti. Curr Opin Genet Dev. 2006 Jun;16(3):282-8.
Fusco F, Pescatore A, Bal E, Ghoul A, Paciolla M, Lioi MB, et al. Alterations of the IKBKG locus and diseases: An update and a report of 13 novel mutations. Hum Mutat. 2008 May;29(5):595-604.
Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D. NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci. 2003 Oct;6(10):1072-8.

Test yourself

A few questions straight from this article.

1 / 10 0 correct

What is the inheritance pattern of incontinentia pigmenti, also called Bloch-Sulzberger syndrome?
Incontinentia pigmenti is a rare X-linked dominantly inherited syndrome that manifests at birth or in early childhood.
How do the cardinal skin lesions of incontinentia pigmenti evolve?
The cardinal feature is progressive skin change, beginning as vesiculobullous lesions and passing through four stages to whorl-like pigmentary lesions.
In what proportion of patients with incontinentia pigmenti are eye findings seen?
Eye findings occur in 35-40% of patients with incontinentia pigmenti, so every suspected case needs a thorough eye examination.
The retinal findings of incontinentia pigmenti arise from which underlying process?
Vascular occlusion underlies the retinal picture, producing avascularity, neovascularisation, haemorrhage, loss of the foveal pit and detachment.
Which ocular abnormality is the most commonly diagnosed eye finding in incontinentia pigmenti?
Retinal detachment is the eye finding most often diagnosed in incontinentia pigmenti.
Retinal detachment in incontinentia pigmenti nearly always occurs within which age window?
Detachments nearly always occur within six years of age and are relatively rare in older patients.
How should the avascular peripheral retina of incontinentia pigmenti be treated?
The avascular retina is treated much as in retinopathy of prematurity, with laser photocoagulation or cryotherapy of the avascular zone.
What is the current status of intravitreal anti-VEGF therapy in incontinentia pigmenti?
Intravitreal anti-VEGF has been investigated and may prove promising, but it has not become the standard of care.
Which feature separates incontinentia pigmenti from retinopathy of prematurity, FEVR, sickle cell retinopathy and the Norrie spectrum?
These conditions share the retinal picture, but none of them is associated with the skin findings of incontinentia pigmenti.
Naegeli syndrome can resemble the skin lesions of incontinentia pigmenti. How does it differ?
Naegeli syndrome affects skin and ectoderm and can look like the skin lesions of incontinentia pigmenti, but it does not produce significant eye findings.