We describe a case of Omenn syndrome displaying exudative erythroderma and other characteristic features, including alopecia, absent B and naïve T cells, hyper immunoglobulin E levels, and eosinophilia. A pathogenic recombination-activating RAG1 homozygous genetic mutation confirmed the diagnosis. She required frequent antibiotics at both treatment and prophylactic doses, which alone did not control her erythroderma, but her high risk of infection precluded the use of systemic agents such as cyclosporine, which would further suppress her already severely compromised immune system. Thrice-weekly topical dilute hypochlorite compresses, combined with skin acidification with a low pH emollient, were initiated to control inflammation and for cutaneous bacterial prophylaxis. She demonstrated a marked improvement in her erythroderma within days after treatment initiation. Further improvement continued with the addition of systemic corticosteroids, with resolution of erythroderma after her first dose. This case reveals for the first time that dilute topical hypochlorite and skin pH restoration holds promise to control severe dermatitis associated with immunodeficiency and inflammatory syndromes with minimal side effects.
- AD —
- atopic dermatitis
- BMT —
- bone marrow transplant
- GvHD —
- graft-versus-host disease
- HOCl —
- Ig —
- IL —
- IV —
Omenn syndrome is a severe combined immunodeficiency syndrome with low to absent B cells, autoreactive T cells with a restricted T-cell receptor repertoire, and normal natural killer cells. In addition to immunodeficiency, Omenn syndrome patients also demonstrate signs of autoimmunity, caused by infiltration of the autoreactive T cells into the skin, liver, and gastrointestinal tract and exhibited by generalized exudative erythroderma early in life. Omenn syndrome, therefore, combines severe immunodeficiency with features of allergic inflammation (eosinophilia, elevated immunoglobulin [Ig] E, increased interleukin [IL] 4, IL-5, and IL-10) and autoimmunity. Hypomorphic mutations in RAG1 and RAG2, causing dysfunctional variable, diversity, and joining gene segment recombination, underlie the majority of Omenn syndrome cases. Without bone marrow transplant (BMT) before 6 months of age, infants with Omenn syndrome usually die of life-threatening infections.
Systemic immunosuppressive medications, such as cyclosporine, can reduce erythroderma but carry a high infection risk in an already immunocompromised host. Indeed, reports of patients treated with cyclosporine were associated with sepsis.1–3 We describe an infant with Omenn syndrome whose erythroderma significantly improved with dilute bleach bath compresses and completely resolved shortly after addition of intravenous (IV) corticosteroids.
A female infant born at 36 5/7 weeks’ gestation exhibited generalized edema, alopecia of hair and eyelashes, and erythematous, shiny taut skin over areas of her trunk and extremities reminiscent of a collodion membrane. Within the first few weeks of life, she developed widespread eczematous dermatitis, marked thickening of skin, and erythroderma (Fig 1A). Newborn screening revealed T-cell lymphopenia and flow cytometry absence of CD19 cells and low numbers of CD3+ (CD4+ and CD8+) cells but normal number of natural killer cells. A T-cell maturation study (CD45 RA/RO flow cytometry analysis) revealed only memory T cells and lack of naïve T cells, and she demonstrated an abnormally low lymphocyte proliferation in response to mitogens. She exhibited a markedly elevated IgE level (up to 767 IU/mL; normal: 0–15 IU/mL at day 60 of life) and eosinophilia (4.79 × 109/L; normal: 0.3–0.90 × 109/L at day 7 of life) but exhibited low IgG at 212 mg/dL (normal: 468–1287 at day 1 of life). Her IgA level was 10 mg/dL (normal: 0 mg/dL at day 1 of life), and her IgM levels were <10 mg/dL (normal: 0–18 mg/dL at day 1 of life). Genetic sequencing revealed a homozygous RAG1 pathogenic mutation, confirming the diagnosis of Omenn syndrome.
Although her rash resembled maternal-fetal graft-versus-host disease (GvHD) (Fig 1A), molecular chimerism studies revealed 98% of peripheral blood lymphocytes were neonate-derived, ruling out maternal engraftment. Despite application every few hours of Aquaphor ointment, her erythroderma and widespread dermatitis persisted. Concerns arose over her ability to maintain epidermal barrier function and to avert thermoregulation instability, dehydration, and eventual hypoalbuminemia. Systemic immunosuppression was considered to improve the dermatitis, but given that she was on extended IV antibiotic treatment of coagulase-negative staphylococcal and Streptococcus viridans bacteremia and presumed meningitis, the risk of infection was deemed too high.
We decided that a regimen of hypochlorite (HOCl) baths would be a reasonable and safe option for this immunocompromised infant. Full-body compresses of dilute sodium HOCl (bleach) (0.005% vol/vol) for 10 minutes were initiated 3 times weekly, followed by rinsing with sterile water, patting dry, and immediately moisturizing with a low-pH emollient cream (CeraVe, New York, New York), with continued application of Aquaphor emollient ointment. Within 5 days (after 2 episodes of dilute HOCl treatments), her erythroderma and exudative scaly patches were markedly reduced (Fig 1B). Her erythroderma then went on to completely resolve after even a single dose of IV methylprednisolone (1 mg/kg), which was added to her treatment regimen. By 3 weeks after initiating dilute HOCl compresses and 13 days after addition of daily methylprednisolone (started at 1 mg/kg and increased to 2 mg/kg), her epidermal barrier was fully intact (Fig 1C), allowing weaning from a humidified incubator. Bicarbonate levels remained normal throughout the course of the bleach bath treatments. She was transitioned to oral prednisone, which was then tapered to a physiologic end point (0.16 mg/kg every 24 hours) with stable skin condition, and bleach baths were discontinued in anticipation of BMT. She was found to have cytomegalovirus viremia, which was treated, and hematopoietic stem cell transplant was performed with a cytomegalovirus-positive, unrelated, matched donor after conditioning at 4 months of age. Engraftment occurred, and she continued to do well, although she was being treated for resultant hypertension, possibly from previous steroids and current posttransplant cyclosporine. She was discharged from the hospital with close follow-up. Her skin remained clear, except for mild hypertrichosis from cyclosporine, and without signs of GvHD 14 weeks after BMT (Fig 1D).
The cutaneous hallmark of Omenn syndrome is a severe exfoliative erythroderma caused by autoreactive oligoclonal T-cell infiltration into the skin, resulting in a severe epidermal barrier defect and subsequent risk of life-threatening bacterial infection and thermoregulatory defects related to poor barrier function. Cyclosporine A, which inhibits the activation of transcription factor nuclear factor of activated T cells, improved the erythroderma of infants with Omenn syndrome but was associated with sepsis and death (Table 1).1,2,4,5 Although systemic cyclosporine was briefly considered for this child, risks of sepsis outweighed benefits, especially as she was undergoing ongoing treatment of bacteremia and presumed meningitis, exhibited elevated liver enzymes, and BMT was not yet in the immediate future. Furthermore, she did not suffer from systemic symptoms such as intractable diarrhea or failure to thrive, which may have benefited from cyclosporine.
Given the cutaneous anti-inflammatory effect of dilute bleach baths as a maintenance intervention for atopic dermatitis (AD),9 a disorder which shares the impaired barrier and T helper 2 cell skewing of Omenn syndrome, we hypothesized that dilute bleach compresses might be an effective means to reduce both skin inflammation and the risk of bacterial infection of Omenn syndrome. Indeed, topical HOCl (dilute bleach) exerts immunomodulatory effects at a molecular level. Sodium HOCl inhibits nuclear factor κ-light-chain-enhancer of activated B cells stimulation by tumor necrosis factor α in human keratinocytes,10 suggesting that it exerts a direct anti-inflammatory action in addition to its antibacterial properties. In mice, topical dilute HOCl baths reduced sequelae of acute radiation dermatitis and improved the epidermal barrier.10 The authors of a recent study demonstrated that just a single week of bleach baths administered twice weekly led to transcriptome changes in inflammatory pathways in skin of humans with AD, and that 12 weeks of this treatment altered epidermal gene expression, suggesting mechanisms by which bleach baths contribute to the barrier improvements observed.11
In addition, stratum corneum acidification reduces barrier abnormalities, eosinophil and mast cell infiltration into the skin, and elicitation of AD in a mouse model,12 leading us to follow the bleach compresses with application of low-pH emollient (initially CeraVe Baby and then transitioned to CeraVe Moisturizing Cream, pH 5.49). In the treatment of Omenn syndrome, discussion of frequent use of emollient is often omitted, but this treatment has been shown to decrease flares and inflammatory signs of AD,13 and our patient continued liberal emollient use throughout her entire hospital stay.
To our knowledge, this is the first report of a topical therapy regimen for the erythroderma of Omenn syndrome. The authors of previous reports discuss various systemic agents; systemic steroids (methylprednisolone) reportedly led to partial and transient improvement in erythroderma and lymph node swelling in 2 patients,2 and in combination with cyclosporine A, ameliorated erythroderma in another (Table 1).7 Although our patient was treated with methylprednisolone during the course of this topical intervention, her erythema had dramatically improved while using the bleach compresses and acidification with emollient, even before initiation of methylprednisolone. During this time, she was also on concurrent treatment doses of antibiotics for bacteremia, which may have contributed anti-inflammatory properties as well. This begs the question of whether, in combination with prophylactic antibiotics, the significant erythroderma of Omenn syndrome can be markedly improved with topical HOCl alone, with or without minimal adjuvant doses of systemic steroids. Because of our results, we suggest that this improvement may be maintained with regular bleach bath compresses, which may be steroid-sparing by allowing intermittent or short-term steroid dosing. Although our patient was a term infant, long-term sequelae of neurodevelopmental delay, such as cerebral palsy, lowered IQ, and motor coordination deficits, as well as hypertension, hyperglycemia, and growth retardation have been reported in premature infants administered even a short course of systemic steroids for bronchopulmonary dysplasia in the neonatal period.14
These modalities (dilute HOCl baths and skin acidification) avert the risks observed with larger scale immunosuppression, while still improving the cutaneous barrier. Although immunosuppressive agents such as cyclosporine play a role in the immediate pretransplant conditioning and posttransplant period, topical regimens may offer benefit in the weeks before and in preparation for transplant. Topical HOCl has been a safe and effective therapy for infants and children with AD, and our study reveals that its utility in rare inflammatory and immunodeficiency diseases merits further investigation.
We report for the first time a child with Omenn syndrome treated with dilute topical HOCl bleach baths, followed by skin emollient acidification, who displayed marked improvement in her erythroderma. Our observation reveals the value of dilute bleach compresses and skin acidification for neonates with immunodeficiency at risk for infection with careful monitoring of systemic acid-base balance.
- Accepted July 20, 2017.
- Address correspondence to Margaret Wat, MD, PhD, Department of Dermatology, University Hospitals Cleveland Medical Center, 11100 Euclid Ave, Cleveland, OH 44106. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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- Copyright © 2018 by the American Academy of Pediatrics