Recrudescence of incontinentia pigmenti presenting as a paraneoplastic syndrome: A natural experiment of NF-kB blockade in an inflammatory malignancy

IP: incontinentia pigmenti IKK: inhibitor kappa kinase INTRODUCTION Incontinentia pigmenti (IP)—an X-linkededominant genodermatosis—results from NF-kB essential modulator/inhibitor kappa kinase (IKK)-gamma gene mutations, rendering the cells unable to activate the NF-kB pathway and highly susceptible to TNF-induced apoptosis. Various clinical findings affect the skin, hair, teeth, nails, eyes, and central nervous system. Blaschkoid skin lesions demonstrate 4 stages: inflammatory, verrucous, hyperpigmented, and hypopigmented/atrophic. Cutaneous progression is attributed to hyperproliferation and necrosis of IKK-gamma-deficient cells with subsequent release of proinflammatory cytokines by neighboring IKK-gamma-positive cells, enhancing apoptosis and resulting in the burnout of disease in infancy. Adult patients may demonstrate residual swirled to reticulated hyperpigmentation. Rare cases of cutaneous IP recrudescence after infancy may result from the stimulation of residual IKK-gammadeficient cells that previously evaded apoptosis, and TNF-a is a potential underlying trigger.


INTRODUCTION
Incontinentia pigmenti (IP)-an X-linkededominant genodermatosis-results from NF-kB essential modulator/inhibitor kappa kinase (IKK)-gamma gene mutations, rendering the cells unable to activate the NF-kB pathway and highly susceptible to TNF-induced apoptosis. 1Various clinical findings affect the skin, hair, teeth, nails, eyes, and central nervous system.Blaschkoid skin lesions demonstrate 4 stages: inflammatory, verrucous, hyperpigmented, and hypopigmented/atrophic.Cutaneous progression is attributed to hyperproliferation and necrosis of IKK-gamma-deficient cells with subsequent release of proinflammatory cytokines by neighboring IKK-gamma-positive cells, enhancing apoptosis and resulting in the burnout of disease in infancy. 1,2Adult patients may demonstrate residual swirled to reticulated hyperpigmentation.Rare cases of cutaneous IP recrudescence after infancy may result from the stimulation of residual IKK-gammadeficient cells that previously evaded apoptosis, and TNF-a is a potential underlying trigger. 2

CASE REPORT
A 35-year-old woman with a history of IP complicated by epilepsy, monocular blindness, conical teeth, and family history of IP (mother, sister, and daughter) presented with epigastric pain status after recently treated Helicobacter pylori infection.She was afebrile with otherwise negative review of systems but had profound anemia (hemoglobin = 5.9 g/dL).
Esophagogastroduodenoscopy and imaging demonstrated gastric adenocarcinoma without any evidence of metastatic disease.The dermatology department was consulted for a pruritic eruption present since admission.Cutaneous examination revealed agminated vesicles and hyperkeratotic plaques overlying reticulated hyperpigmentation (Fig 1, A, B).The results of polymerase chain reaction studies for lesional herpes simplex/varicella zoster virus were negative.Right hip biopsy revealed eosinophilic spongiosis with dyskeratosis and melanophages (Fig malignancy treatment response based on imaging, 5 months after admission, gastrectomy with lymphadenectomy demonstrated adenocarcinoma with lymphovascular/perineural invasion and positive lymph nodes.Postoperatively, no further skin irritation was noted, and CT findings for chest/abdomen/ pelvis were negative for metastatic disease status after adjuvant chemotherapy.The patient remains without disease or skin lesion recurrence 15 months after resection.

DISCUSSION
Cases of cutaneous IP recrudescence in the setting of viral infections and immunizations have been reported in the literature.Recrudescence is thought to be caused by TNF-a-induced stimulation of residual IKK-gamma-deficient cells that are unable to activate the NF-kB pathway and are consequently vulnerable to TNF-induced apoptosis. 2Here, we report a case of paraneoplastic IP recrudescence occurring in the setting of H. pylori-associated gastric adenocarcinoma-a malignancy associated with elevated levels of TNF-a. 3 This novel association was noted in the oldest patient who demonstrated IP recrudescence in the English medical literature.
The NF-kB pathway is an attractive oncologic therapeutic target as its inhibition theoretically impedes survival signals in malignant cells. 4In nonmutated cells, NF-kB remains inactive in the cytoplasm through its association with IkB.In response to stimuli, IkB is phosphorylated by IKK, allowing degradation of IkB and nuclear translocation of NF-kB.Current NF-kB pathway therapeutic targets include inhibition of upstream IKK, inhibition of IkB proteasomal degradation, and repression of NF-kB binding to DNA. 5 IP serves as a natural model of NF-kB blockade through upstream IKK inhibition, demonstrating sensitivity of cells to apoptosis when exposed to proinflammatory cytokines.Furthermore, paraneoplastic IP recrudescence due to gastric adenocarcinoma emphasizes the potential for directed IKK-g-deficient cell apoptosis in the presence of malignancyinduced TNF-a signaling.