Correspondence Address:
Nouf Al-Farsi
Department of Ophthalmology, Sultan Qaboos University Hospital, P.O. Box 38, PC 123, Al Koud, Seeb, Muscat
Oman

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Incontinentia pigmenti (IP) also known as Bloch-Sulzberger syndrome is a rare X-linked dominant genetic disorder associated with mutations in the inhibitor of nuclear factor-kB kinase subunit g (IKBKG), also called NF-kB essential modulator (NEMO) gene located on the chromosome band Xq28.[1] This gene plays a major role in regulating cell signal transduction pathway, which is crucial in the formation of ectodermal tissues found in many organ systems such as the skin (>90%), ocular (77%), dental (65%), and central nervous system (30%).[1]

The mutated NEMO gene is thought to induce an inflammatory reaction in various body cells such as the skin and vascular endothelial cells. As a consequence of this mutation, these cells abnormally increase their expression of chemotactic factors which specifically attract and activate eosinophils. The aggressive inflammation of endothelial cells in blood vessels will eventually lead to vascular occlusion and tissue ischemia seen on retinal examination. This also explains why patients with IP have high levels of eosinophils in the blood and on histological biopsies of skin lesions.

Cutaneous lesions which follow the lines of Blaschko are highly diagnostic and start to appear within the first few weeks of life up to 18 months of age.[1] It can be classified into four stages: vesicular erythema, verrucous lesions, hyperpigmentation, and eventually atrophic lesions.[2] Skin biopsy and genetic testing are the gold standards to confirm the clinical diagnosis.[3]

Ocular manifestations can be divided into retinal and nonretinal signs. They can vary from corneal verticillata, microphthalmia, strabismus, and congenital cataract to optic nerve atrophy. However, retinal findings usually start with incomplete retinal vascularization areas leading to neovascularization, retinal hemorrhages, and eventually retinal detachment (RD) leading to the classical feature of retrolental fibroplasia if left untreated.[4] The fovea has been involved in some cases showing hypoplasia or avascularization. Multifocal hyper-or hypopigmented lesions of the RPE have also been reported.[4] Out of these, RD remains to be the most feared sight-threatening complication.

It is very crucial to detect retinopathies early in IP for prompt management and vision-saving measures. It is recommended to initiate ophthalmic evaluation, once the clinical diagnosis of cutaneous lesions is made. This is quite different than the screening system used in retinopathy of prematurity (ROP) which specifies preterm newborns according to gestational age and birth weight, therefore, none can be missed. IP ophthalmic screening examination is usually dependent on other systemic manifestations of the disease such as the peculiar skin lesions which do not necessarily appear at birth.[1] This can delay detection and early intervention. A retrospective review on 61 patients diagnosed with IP with a median age of diagnosis of 3.1 months, retinal anomalies were found in 61.5%, out of them 20.5% had RD and 6.6% had an end-stage retinal disease.[3] This highlights the fact that IP retinopathy can present too early in life and can be sight-threatening if missed.

The current guidelines suggest that all patients should undergo fundoscopic examination at baseline with examination under anesthesia and fundus fluorescein angiography (FFA). In a case series, 26 patients diagnosed with IP had a screening examination for retinopathy and FFA. Three cases showed abnormal FFA although they had normal fundus examination initially.[5] FFA should be done in the first screening visit to all IP patients regardless of fundus examination findings. This also is quite different from ROP, where FFA is rarely if ever needed.

For subsequent follow-ups, ROP ophthalmic screening can be terminated whenever the infant is no longer at risk of sight-threatening events or when the retina is fully vascularized with or without treatment. To the contrary, IP patients need to be followed up for life. If the initial examination is normal, then follow-up should be at 1, 2, 3, 6, 12, 18, and 24 months of age and then annually lifelong.[2] A retrospective observational cohort study showed a bimodal distribution of RD in IP according to patients age; patients younger than 2.5 years developed tractional RD, while rhegmatogenous RD was more common in patients of 14 years of age or older.[6] This emphasizes the importance of lifelong follow-up of IP patients by an ophthalmologist.

Peng et al.[3] have developed a staging system for IP which is quite similar to that of ROP based on the clinical findings but not utilizing the (zone) definition applied in ROP. Stage1 – RPE changes only, Stage 2 – retinal vascular abnormalities, Stage 3 – retinopathy with neovascularization or hemorrhage, Stage 4 – RD (4-a partial and 4-b total RD), and Stage 5 – ocular complications such as phthisis bulbi and secondary glaucoma.

Despite the differences in disease pathophysiology of IP and ROP, both eventually lead to retinal ischemia which enhances intraocular vascular endothelial growth factor (VEGF) levels and neovascularization as a consequence. Therefore, it remains to be safe take to treat them similarly. Current options of treatment for almost all retinopathies (caused by ROP, IP, and other etiologies) to suppress retinal neovascularization includes observation, laser photocoagulation, and intravitreal anti-VEGF injections.[5]

These treatment options are well-researched and practiced worldwide when treating ROP. A recent study of ROP patients found that primary anti-VEGF was superior to laser photocoagulation in terms of outcomes, especially in active posterior pole disease.[7] However, in IP, anti-VEGF was only recently introduced as a primary or adjunct therapy modality. Ranibizumab (0.025 ml) IVI showed a favorable outcome after a single injection in a 5-week-old term twins with IP presented with bilateral stage 3 retinal disease.[8] Similar results were found in a 13-week female after injecting bevacizumab which suppressed neovascularization. However, a 6-week-old infant with IP and impending RD in one eye has unfortunately developed necrotizing enterocolitis shortly after using bevacizumab.[9] This was also noted in ROP patients as bevacizumab is known to have more systemic side effects compared to ranibizumab.[10]

In conclusion, IP and retinopathy of prematurity are quite similar retinopathies and can be managed in the same manner. However, one must be cautious while managing them, keeping in mind, the differences between the two conditions which are highlighted in [Table 1]. The scarcity of IP cases makes it harder to conclude clear guidelines with high confidence. Further research in patients with IP is definitely needed to explore better options for screening and treatment.{Table 1}

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