IP, with an estimated birth prevalence of 1–9/1,000,000 (http://www.orpha.net/orphacom), is an X-linked dominant disease [6]. Because males lack a compensatory healthy X chromosome, the common deletion of IKBKG is lethal in males and the resulting disease form is mainly seen in females.
IP is caused by mutations in the IKBKG (inhibitor of kappa B kinase gamma) gene, also known as NEMO (nuclear factor-kappa-B essential modulator), located on Xq28. The encoded protein I-kappa-B kinase-gamma is involved in the activation of NF-κB, thus the regulation of apoptosis, inflammation, and immunity. Most of the cases have “de novo” deletions of exons 4–10, resulting in complete loss of encoded protein function [5, 6].
The phenotypic expression can range from mild skin involvements to severe neuro-ophthalmological symptoms, thus clinical variations, even in the same family, can be observed. This variability of expressivity is mainly caused by lyonization (X-inactivation) that leads to functional mosaicism [6, 7,8,9,10].
Dermatological findings develop in the first weeks of life and are generally the first to be observed, and as our patient, most patients present them.
80% of the cases have dental anomalies, making dental findings are the most seen after dermatological ones. On the contrary to dermatological, dental anomalies last for life and have a different diagnostic significance [9,10,11].
Ocular involvement is not common, around 35% of the cases are thought to have it. Strabismus, optic nerve atrophy, conjunctival pigmentation, iris hypoplasia, nystagmus, and uveitis are important non-retinal findings. Foveal hypoplasia, avascular retina, neovascularization, vitreous hemorrhage, and fibrovascular proliferation are important retinal findings, and they are usually associated with vascular abnormalities. Retinal detachment and blindness can be observed in advanced cases.
Retinal lesions are most usually observed in the first 12 months, thus making ophthalmological follow-ups during this period highly important. Non-retinal lesions tend to occur later, within age 2 years [12, 13].
Differential diagnosis of IP varies within different cutaneous stages of the disease. During the first vesicular stage, newborn vesiculobullous diseases should be suspected, infections such as bullous impetigo, herpes simplex, varicella, or immunological diseases such as dermatitis herpetiformis, epidermolysis bullosa acquisita, bullous pemphigus, neonatal pemphigus vulgaris should be investigated. Langerhans cell histiocytosis can also manifest as papules and vesicles during the newborn period. Additionally, bullous mastocytosis can manifest as localized erythema and bullae in the first year of life [14].
This variant that we detected in our study has not been reported. c.172_173delAA (p.Asn58SerfsTer79) variant was not found in healthy population, but its locus is covered in gnomAD exomes and genomes databases. This variant is located in exon 2 in IKBKG and causes a terminated protein. Therefore, we evaluated this deletion pathogenic according to the ACMG guideline [15].