Nemo Gene Mutation

Vishanna Balbirsingh

Incontinentia Pigmenti (IP), also called Bloch-Sulzberger syndrome is a rare genetic disorder primarily caused by mutations in the NEMO gene (Nuclear Factor-kappa B Essential Modulator) also known as the IKBKG gene. It is a primary immunodeficiency disorder that affects the skin, hair, teeth, eyes, and central nervous system (1).

Causes

IP is an x-linked disorder leading to abnormal function of the protein that IKBKG codes for. This protein is involved in the nuclear factor-kappa B signaling pathway which is important for immune response, cell survival and inflammation regulation (1). It is more commonly seen in females because it is usually fatal in male infants. Females survive due to lyonization, common of many X-linked disorders (2).

Clinical features

The condition results in skin changes including blisters on the trunk and extremities, wart-like papules and hypopigmentation/hyperpigmentation (3). Affected people may also have thin hair, abnormally formed teeth. In some people, the central nervous system is affected leading to mental deficiency, spasticity or seizures (4).

Although some patients have normal vision, around 35% of patients with IP develop ophthalmic manifestations of disease (5). Structural abnormalities include inner retinal thinning, optic nerve atrophy, and irregularities in the outer plexiform layer. A blunted foveal pit is characteristic of IP (6). Vascular abnormalities include abnormal anastomoses, microaneurysms and areas of nonperfusion (5)

Diagnosis

Patients are identified after genetic testing reveals mutations in the gene. As the disease manifests in mostly retinal abnormalities, assessment of the retina through slit-lamp examination, imaging and optical coherence tomography may be useful (7).

Management

There is no cure for IP, management focuses on preventing complications and managing symptoms. Dermatology input including topical corticosteroids may reduce inflammation in the skin (8). Avascular retina should be treated with laser photocoagulation (or cryotherapy) (9). Regular retina examinations should be performed to monitor the occurrence of retinal detachments and surgical repair should be considered if appropriate. Research surrounding intravitreal anti-vascular endothelial growth factor is growing and may influence future treatment (10).

References

1.            Yadlapati S, Tripathy K. Incontinentia Pigmenti (Bloch-Sulzberger Syndrome). In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [cited 2025 Jan 23]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK578194/

2.            Ardelean D, Pope E. Incontinentia Pigmenti in Boys: A Series and Review of the Literature. Pediatr Dermatol [Internet]. 2006 Nov [cited 2025 Jan 25];23(6):523–7. Available from: https://onlinelibrary.wiley.com/doi/10.1111/j.1525-1470.2006.00302.x

3.            Scheuerle AE, Ursini MV. Incontinentia Pigmenti. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2025 Jan 25]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1472/

4.            Meuwissen MEC, Mancini GMS. Neurological findings in incontinentia pigmenti; a review. Eur J Med Genet [Internet]. 2012 May [cited 2025 Jan 25];55(5):323–31. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1769721212001346

5.            Liu TYA, Han IC, Goldberg MF, Linz MO, Chen CJ, Scott AW. Multimodal Retinal Imaging in Incontinentia Pigmenti Including Optical Coherence Tomography Angiography: Findings From an Older Cohort With Mild Phenotype. JAMA Ophthalmol [Internet]. 2018 May 1 [cited 2025 Jan 25];136(5):467. Available from: http://archopht.jamanetwork.com/article.aspx?doi=10.1001/jamaophthalmol.2018.0475

6.            Basilius J, Young MP, Michaelis TC, Hobbs R, Jenkins G, Hartnett ME. Structural Abnormalities of the Inner Macula in Incontinentia Pigmenti. JAMA Ophthalmol [Internet]. 2015 Sep 1 [cited 2025 Jan 25];133(9):1067. Available from: http://archopht.jamanetwork.com/article.aspx?doi=10.1001/jamaophthalmol.2015.1700

7.            Han IC. Retinal Vascular Disease in Incontinentia Pigmenti is the Rule rather than the Exception. Ophthalmol Retina [Internet]. 2022 Dec [cited 2025 Jan 25];6(12):1111–2. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2468653022004535

8.            Tomotaki S, Shibasaki J, Yunoki Y, Kishigami M, Imagawa T, Aida N, et al. Effectiveness of Corticosteroid Therapy for Acute Neurological Symptoms in Incontinentia Pigmenti. Pediatr Neurol [Internet]. 2016 Mar [cited 2025 Jan 25];56:55–8. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0887899415300333

9.            Nguyen JK, Brady-McCreery KM. Laser photocoagulation in preproliferative retinopathy of incontinentia pigmenti. J Am Assoc Pediatr Ophthalmol Strabismus [Internet]. 2001 Aug [cited 2025 Jan 25];5(4):258–9. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1091853101255426

10.         Cernichiaro-Espinosa LA, Patel NA, Bauer MS, Negron CI, Fallas B, Pogrebniak A, et al. Revascularization After Intravitreal Bevacizumab and Laser Therapy of Bilateral Retinal Vascular Occlusions in Incontinentia Pigmenti (Bloch-Sulzberger Syndrome). Ophthalmic Surg Lasers Imaging Retina [Internet]. 2019 Feb [cited 2025 Jan 25];50(2). Available from: https://journals.healio.com/doi/10.3928/23258160-20190129-16

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