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December 2015

IKBKG Mutation With Incontinentia Pigmenti and Ring-Enhancing Encephalopathy

Author Affiliations
  • 1Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas
  • 2Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas
  • 3Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas
  • 4Department of Pathology, The University of Texas Southwestern Medical Center, Dallas
  • 5Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas
  • 6Eugene McDermott Center for Human Growth & Development/Center for Human Genetics, The University of Texas Southwestern Medical Center, Dallas
  • 7Department of Physiology, The University of Texas Southwestern Medical Center, Dallas
  • 8Rare Brain Disorders Program, The University of Texas Southwestern Medical Center, Dallas
JAMA Neurol. 2015;72(12):1533-1535. doi:10.1001/jamaneurol.2015.2795

Incontinentia pigmenti (IP, Bloch-Sulzberger syndrome) is an X-linked dominant genodermatosis affecting skin and other organs, including the brain, with variable expressivity. Incontinentia pigmenti results from mutations in the inhibitor of κ-β-kinase-γ gene (IKBKG), which is located on Xq28. Deletions in this gene result in loss of function, leading to a wide variety of manifestations.1 This mutation is often lethal in males, resulting in miscarriage of male fetuses. Previously proposed revised diagnostic criteria2 included as major criteria any of 4 types of IP skin lesions and several minor criteria including anomalies of the brain, eyes, oral cavity, breasts, nipples, hair, and nails in a typical context of multiple male miscarriages and characteristic skin histopathology findings.

Report of a Case

An infant girl, the product of consanguineous parents, presented at birth with erythematous vesicles on her hands, progressing to scaly, erythematous plaques on her head, neck, trunk, and extremities in a blaschkoid pattern. There were no neurological symptoms. Initial concern for infection led to several investigations. Results from blood culture and herpes simplex virus culture of a vesicle were negative. Cerebrospinal fluid showed elevated protein level of 0.063 g/dL (range, 0.015-0.06 g/dL; to convert to grams per liter, multiply by 10), glucose level of 52 mg/dL, and 0.004 nucleated cells/L, with negative herpes simplex virus polymerase chain reaction results. Aspartate aminotransferase level was elevated to 1355 U/L (range, 10-80 units/L; to convert to microkatals per liter, multiply by 0.0167), and the alanine aminotransferase level was elevated to 807 U/L (range, 10-50 U/L; to convert to microkatals per liter, multiply by 0.0167).

Fundoscopy revealed bilateral preretinal and retinal hemorrhages, extending to the maculae, as commonly seen in vaginally delivered infants. Brain magnetic resonance imaging showed multiple areas of restricted diffusion and intraparenchymal and leptomeningeal enhancement resembling hemophagocytic lymphohistiocytosis (Figure). DNA sequencing for a panel of genes associated with hemophagocytic lymphohistiocytosis was negative. Skin histopathological examination revealed dense inflammatory infiltrate with a myriad of eosinophils, prominent spongiosis with intraepidermal vesicles containing eosinophils, and several necrotic keratinocytes, consistent with the inflammatory stage of IP. The child harbored a common known pathogenic deletion in IKBKG, also known as activator of NF-κ-β or NEMO.

Figure.  Manifestations of Incontinentia Pigmenti Associated With IKBKG Deletion
Manifestations of Incontinentia Pigmenti Associated With IKBKG Deletion

A, Rash on the torso. B, Rash in blaschkoid pattern in the upper extremity. C and D, Skin biopsy showing inflammatory stage lesions typical of incontinentia pigmenti (hematoxylin-eosin; C, original magnification ×100 and D, original magnification ×400). The white arrowheads indicate dyskeratotic keratinocytes; red arrowheads, spongiosis; blue arrowheads, intraepidermal and dermal inflammatory infiltrate including eosinophils and lymphocytes; black arrowheads, intraepidermal vesicles containing eosinophils; and yellow arrowhead, normal skin at the edge of the biopsy for comparison. E, The first 4 columns of images show diffusion-weighted axial magnetic resonance imaging (MRI) scans obtained across the entire encephalon demonstrating areas of restricted diffusion throughout the right cerebral hemispheres. The images in the fifth column show postcontrast axial fluid-attenuated inversion recovery MRI images illustrating ring enhancement in areas of restricted diffusion.

This study was approved by the University of Texas Southwestern Medical Center institutional review board.


Skin manifestations are commonly the first symptom and occur in nearly all patients with IP. They follow Blaschko lines. Our patient had inflammatory lesions (Figure). Eye abnormalities include retinal anomalies, such as telangiectasia, hemorrhage, arteriovenous anastomoses, neovascularization, and retinal avascularity, or anomalies involving vitreous and lens, microphthalmia, and cataracts. Minor criteria include skin appendage abnormalities including the absence of pilosebaceous glands; alopecia; sparse, wooly hair; anomalies of eyebrows and eyelashes; nail pitting; dystrophy; and subungual or periungual tumors.3 Nipple and dental anomalies may also be present. Neurological manifestations occur in the first month of life in two-thirds of cases with neurological involvement, which comprise as much as one-third of all IP cases.4 They range from a single seizure to psychomotor delay, learning disabilities, hemiplegia, epilepsy, cerebellar ataxia, microcephaly, childhood encephalomyelitis, and strokelike episodes. Magnetic resonance imaging may reveal white matter and corpus callosum abnormalities, cortical malformations, cerebral atrophy, and cerebral or cerebellar hemorrhage.5,6 Although strokelike lesions secondary to focal cortical and white matter necrosis in a nonvascular distribution have been reported in IP, ring enhancement is unusual. Our patient manifested ring enhancement in areas of restricted diffusion together with subtle, diffuse intraparenchymal, cerebellar, and leptomeningeal enhancement.


The rarity of IP together with its myriad clinical presentations poses a significant diagnostic challenge. The presentation of IP may mimic other blaschkoid pigmentary disorders such as hypomelanosis of Ito, focal dermal hypoplasia (Goltz syndrome), or herpes simplex virus infection. The neurological syndrome of IP is even less specific. In the absence of cerebral Citrobacter or fungal infection, the diffuse radially distributed ring-enhancement appearance of our case by magnetic resonance imaging is most suggestive of cellular loss along migrational trajectories.

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Article Information

Corresponding Author: Juan M. Pascual, MD, PhD, Rare Brain Disorders Program, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Mail Code 8813, Dallas, TX 75390-8813 (juan.pascual@utsouthwestern.edu).

Conflict of Interest Disclosures: None reported.

Funding/Support: Dr Pascual is supported by National Institutes of Health grants NS077015, NS078059, RR002584, and RR024982.

Role of the Funder/Sponsor: The National Institutes of Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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