Dermatologic Therapy | 2021
The potential role of propranolol in incontinentia pigmenti
Abstract
Dear Editor, Incontinentia pigmenti (IP) is a rare X-linked dominant inherited genodermatosis, caused by mutations in the nuclear factor-κB essential modulator (NEMO) gene, that can affect the skin and many other tissues. In particular, central nervous system (CNS) and ophthalmologic manifestations can be severe. In case of retinal involvement, which often coexist with CNS complications, the lesions are due to ischemia caused by vaso-occlusive events, followed by subsequent compensatory vasoproliferation, leading to potentially blinding complications. The ischemic process and subsequent neovascularization have been observed in both IP retinopathy and retinopathy of prematurity (ROP), with similar clinical complications, such as hemorrhages, and blindness. The β-adrenergic system is involved in the hypoxiainduced neoangiogenesis in the ROP and also in other diseases, such as infantile hemangiomas (IHs), and cancers. In both ROP and IHs, hypoxia develops after a first ischemic phase and induces an increased catecholamine release and upregulation of β3-adrenergic receptor (β3-ARs). The interaction between catecholamines and β-ARs (the β2-ARs and the upregulated β3-ARs) stimulates the pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), and subsequently the vascular proliferation (proliferative phase). As nuclear factor-κB is involved in the transduction system of the messages received by the VEGF receptor, the VEGF receptor may have a role in the microvascular changes in patients affected by IP. The nonselective β-AR antagonist propranolol is the first-line treatment in IHs during the proliferative phase and the inhibition of the VEGF production plays a central role in the drug s action. Propranolol in IHs is usually safe in infants older than 5 weeks and has shown an acceptable safety profile also in children younger than 5 weeks, with special precautions. The inhibition of VEGF through blockade of the β2-AR could also be effective in treating ROP, considering that also in this disease the retinal neoangiogenesis is mediated by VEGF and both β1and β2-ARs are expressed in the retina. A randomized controlled trial has yielded good results in terms of efficacy in preterm newborns (GA < 32 weeks) in stage 2 ROP without plus in zone II, treated with oral propranolol (0.25 or 0.5 mg/kg/6 hours). Newborns treated with oral propranolol showed significantly decreased ROP progression to stage 3 and stage 3 with plus and none of the treated newborns progressed to stage 4. However, 19.2% of the treated newborns had serious adverse effects (hypotension, bradycardia), in conjunction with episodes of sepsis, anesthesia induction, or tracheal stimulation. Filippi et al. have obtained similar efficacy results, but without side effects, using propranolol 0.2% eye micro-drops in preterm newborns (GA < 32 weeks) with stage 1 ROP. The common pathogenetic role of vasoproliferation induced by ischemia/hypoxia in IHs, ROP and retinal involvement in IP and the excellent outcome of propranolol in treating IHs and ROP, strongly suggest that propranolol could be a new therapeutic strategy in patients suffering from IP with ocular involvement. Moreover, considering the role of ischemia in case of CNS complications and the recent demonstration that propranolol not only counteracts vascular proliferation but also improves the neuronal function in a mouse model, propranolol can be a promising drug also in case of IP with CNS symptoms. To establish the correct timing of the treatment, a multidisciplinary evaluation appears to be essential, considering that the use of propranolol during the ischemic phase, when the levels of proangiogenic factors are low, probably is not useful or even harmful. On the contrary, the β-ARs blockade during the neovascularization is probably an appropriate strategy to counteract the progression of the retinopathy. Further investigations on the pathogenetic mechanisms are recommended before activating clinical trials, using either systemic or topic propranolol, that are necessary to confirm this hypothesis.