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The heartrending aspects of incontinentia pigmenti

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By Warren R. Heymann, MD
March 12, 2018

incontinentia pigmenti

Incontinentia pigmenti (IP, aka Bloch-Sulzberger syndrome) provides lessons in genetics, immunology, and neuroectodermal development. Frankly, I have never given much (if any) thought about its cardiovascular manifestations. Albeit rare, they are part of the spectrum of IP.

IP is a rare neuroectodermal dysplasia caused by a defect in the IKBKG gene (formerly known as NEMO). There are approximately 28 new cases per year worldwide; 65% to 75% are sporadic mutations, and 25% to 35% are familial. It is usually lethal in males, but females survive because of X-inactivation mosaicism. The disorder is typically identified by unique skin findings, a series of four stages (vesiculobullous, verrucous, Blaschkoid hyperpigmentation, atrophic hypopigmentation) that emerge throughout the first years of life. The central nervous system manifestations in the eye (retinal hypervascularization and detachment, strabismus, cataracts, optic atrophy, retinal pigmentary abnormalities, and microphthalmia) and brain (seizures, neurocognitive impairment) cause the most disability. Scarring alopecia, dystrophic nails, and teeth abnormalities (hypodontia, microdontia, abnormally shaped, delayed eruption or impaction) occur, and there can be other systemic involvement, such as eosinophilia. (1,2)

I was not aware of cardiovascular issues of IP until I read the article by Onnis et al, reporting the case of a 9-day-old neonate with IP (manifested by classical Blaschkoid vesiculobullous and hyperkeratotic lesions, and confirmed molecularly with deletions of exons 4-10 of the IKBKG gene) who presented with transient reversible pulmonary hypertension. She was dyspneic with severe pulmonary hypertension without primary pulmonary disease. Echocardiography demonstrated marked tricuspid regurgitation and bidirectional atrial shunting. She improved with administration of sildenafil and bosentan. (3)

Yasuda et al reported the case of a 2-month-old female with IP, neonatal seizures, multiple cerebral infarctions, and hypereosinophilia, who was diagnosed with fatal pulmonary arterial hypertension, expiring at age 5 months. (4) In both cases the authors speculated that modulation of nuclear factor-kB signaling may be involved because it is a key transcription factor involved in in tissue remodeling mediated by inflammatory and fibroproliferative responses. Increased levels of endothelin, a powerful pulmonary vasoconstrictor, or other cytokines such as bone morphogenic protein receptor 2, and nitric oxide, could all contribute to endothelial apoptosis, resulting in a microvasculopathy. (3,4). It has also been speculated that the VEGF receptor may be involved in microvascular pathology because NF-kB also performs its function through this receptor. This microangiopathy could also be responsible for retinal and neurologic manifestations. (3)

This microvasculopathy is presumably etiologic in the case of a 16-year-old female with IP and peripheral vascular disease presenting as cold, cyanotic lower extremities. Clinically, her presentation mimicked vasculitis — the autoimmune work-up was unremarkable; no skin biopsy was performed. (5)

Endomyocardial fibrosis (EMF) has been reported in IP. EMF causes restriction of one or both ventricles, eventually leading to fulminant cardiac insufficiency. (6) Although there is no clear consensus on the pathogenesis of EMF, of the three main hypotheses (eosinophilia/parasitic, diet/toxin, and genetic predisposition) (7), presumably the eosinophilia of IP is the most likely etiologic culprit.

My heart goes out to patients (and families) with severe IP, now even more so with the awareness of severe cardiovascular complications. As I am writing this, Valentine’s Day is literally an hour away. Perhaps we can all show some heart by supporting the Incontinentia Pigmenti International Foundation (www.ipif.org) to further research to further unravel the complexities of this disease.*

1. Greene-Roethke C. Incontinentia pigmenti: A summary review of this rare ectodermal dysplasia with neurologic manifestations, including treatment protocols. J Pediatr Health Care 2017; 31: e45-52.
Scheuerle AE, Ursini M. Incontinentia pigmenti. In Adam MP, et al (Eds). GeneReviews, updated December 21, 2017.
2. Onnis G, et al. Cardiopulmonary anomalies in incontinentia pigmenti patients. Int J Dermatol 2018; 57: 40-5.
Yasuda K, et al. Fatal pulmonary arterial hypertension in an infant girl with incontinentia pigmenti. Pediatr Int 2016; 58: 394-6.
3. Beccastrini E, et al. Arterial occlusion mimicking vasculitis in a patient with incontinentia pigmenti. Autoimm Highlights 2013; 4: 63-5.
4. Wood AE, et al. Mitral annuloplasty in endomyocardial fibrosis: An alternative to valve replacement. Ann Thorac Surg 1982: 34: 446-51.
5. Beaton A, Mocumbi AO. Diagnosis and management of endomyocardial fibrosis. Cardiol Clin 2017; 35: 87-98.

*My wife, Rhonda Schnur, MD, is on the Scientific Advisory Council of the IPIF

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