THE SYNDROME PAGE Pediatric Dermatology Vol. 9 No. 4 410-4B
Editors: Susan B. MaUory, M.D., and Bernice R. Krafchik, M.B., Ch.B., F.R.C.P.(C)
What Syndrome Is This?
J12 years. Note the alope-
Figure 1. The f
^. •••- / i \ V Address correspondence to John G. Roth, M.D., 177 Burt Road, Lexington, KY 40503.
410
Figure 3. Lichenified plaques on the hands.
The Syndrome Page 411
The Hyperimmunoglobulin E Syndrome In February 1991 he was hospitalized with worsening of his dermatitis, and a right comeal ulcer that progressed to perforation and required corneal transplant. In addition to severe dermatitis, physical examination revealed extensive alopecia and coarse facia! features (Figs. 2 and 3). Punched-out erosions were present in the groin and over large areas of the back and buttocks (Fig. 4). There was periungual inflammation with onychodystrophy of all nails. Laboratory data during this hospitalization included a white blood cell count of 15.8 K/|xl with 61% segments, 4% bands, 11% lymphocytes, 14% monocytes, and 8% eosinophils. Immunoglobulin levels were IgG 2090 mg/dl (normal 574-1484 mg/ dl), IgM 30 mg/dl (50-232 mg/dl), IgA 385 mg/dl (40212 mg/dl), and IgE 13,000 mg/dl (30-250 mg/dl). Complement values were C3 58 mg/dl (89-195 mg/ dl) and C4 41 mg/dl (10-40 mg/dl). A hepatitis profile was negative, as was a human immunodeficiency virus titer. Skin cultures grew S. aureus and herpes simplex vims type 1. An IgE antistaphylococcal antibody determination showed 41.7% binding (control serum 3.4% binding). On previous occasions a defect in neutrophil chemotaxis had been demonstrated.
Figure 4. Dermatitis and excoriations on the torso. A 12-year-old boy developed severe dermatitis at 1 month of age that required daiiy application of topical steroids, and antibiotics for secondary infection. At 8 months, and again at 11 months of age, he was hospitalized for failure to thrive, vomiting, and wheezing. At 18 months he was hospitalized with disseminated eczema herpeticum followed by Pseudomonas sepsis. He then developed necrotizing left temporal and cephalic vein thrombophlebitis requiring fasciotomy and scalp debridement with grafting. Additional medical problems during that hospitalization were Staphylococcus aureus sepsis, meningitis, and left middle cerebral artery arteritis. He subsequently had two episodes of pneomococcal pneumonia. Throughout this time he had a recalcitrant, intensely pruritic dermatitis requiring daily topical steroids and oral antihistamines, and continuous dicloxacillin therapy for infection (Fig. 1).
THE HYPERIMMUNOGLOBULIN E SYNDROME The hyperimmunoglobulin E syndrome is a rare disorder characterized by a markedly elevated serum IgE level, chronic dermatitis, intense pruritus, and recurrent serious infections. In 1966 two fairskioned, red-haired females were described with severe eczema, recurrent sinopulmonary infections, and staphylococcal abscesses. The authors suggested the term Job's syndrome for these patients because of the remarkable absence of inflammation in the abscesses, resembling the description in the Book of Job (I). In 1972 two male patients were reported with similar findings in addition to coarse facies, recurrent skin, long and joint abscesses, extremely high serum immunoglobulin levels, and positive immediate cutaneous hypersensitivity reactions to S. aureus and Candida albicans (2). Ntimerous subsequent reports have documented this syndrome in individuals of both sexes with a variety of hair colors and diverse racial backgrounds. Features common to these patients are extremely ele-
412 Pediatric Dennatoiogy VoL 9 No. 4 December 1992 vated serum IgE levels, recurrent bacterial, fungal, and viral infections, and chronic dermatitis (3). The hyperimmunoglobulin E syndrome has become the standard designation for this disorder. The ?tge of onset of dermatitis is quite variable, but the eruption often develops within the first six weeks of life (1). Diffuse cutaneous herpes simplex or varicella may occur early (4), but deep-seated bacterial infections are generally not a prominent problem until after 6 months of age. The major organism is usually S. aureus; however, other bacterial pathogens are Haemophilus influenzae, group A Streptococcus, Escherichia coli, and Pseudomonas. Cutaneous infections with nonbacterial organisms are quite common, the most frequent being C. aibicans. Later, recurrent frequent episodes of herpes simplex involving mucosal and cutaneous surfaces may be complicated by herpetic keratoconjunctivitis (5). The differential diagnosis includes severe atopic dermatitis and primary immunodeficiencies such as hypogammaglobulinemia, Wiscott-Aldrich syndrome, and DeGeorge syndrome. The most difficult differentiation is with severe atopic dermatitis (6,7). Staphylococcus aureus infections in atopic dermatitis tend to be superficial; however, in hyperimmunoglobulin E syndrome they are more serious and deep seated. Patients with hyperimmunoglobulin E syndrome have a coarse facies manifested as a broad nasal bridge, prominent nose, and irregularly proportioned cheeks and jaw. Those with both diseases can have very high serum IgE levels and eosinophilia. Additional clinical complications of the hyperimmunoglobulin E syndrome that are not usually found in atopic dermatitis are nonstaphylococcal infections, osteoporosis, vernal conjunctivitis, and pyoderma gangrenosum. The most common laboratory abnormalities in the hyperimmunoglobulin E syndrome are a markedly elevated serum IgE level and peripheral eosinophilia (1,8). Eosinophils can account for as much as 40% to 50% of the differential, with total counts as high as 6600 K/jil. Serum IgG, IgM, IgA, C3, and C4 levels are usually normal. The most important laboratory finding is IgE antibody directed against S. aureus (1). This test is relatively specific in confirming the diagnosis (1). Immunoglobulin antibody also can be directed against C. aibicans, but this finding is less specific. Serum from patients with this syndrome may contain IgG antibody against IgE, but this antibody is not unique to the hyperimmunoglobulin syndrome (9), and nor are the neutrophil chemotactic defects, which probably
are not due to a primary defect in the leukocyte (10). Management of patients with the hyperimmunoglobulin E syndrome is difficult. Topical steroids and histamines are used for the pruritus and dermatitis but are often ineffective. The most effective treatment for S. aureus infections is dicloxacillin (1). Levamisole, ascorbic acid, cimetidine, interferon gamma, and transfer factor all have been reported to improve neutrophil chemotaxis (5,11). Intravenous gammaglobulin and plasmapheresis have been helpful in managing patients with severe disease (12). Although the beneficial effects are of short duration, these modalities should be used for patients who have failed more conservative approaches. A single case report described successful treatment with isotretinoin (13). The long-term prognosis of this disease is not known. Monitoring and prompt treatment of bacterial infections improve the course of the disease. Two case reports associated malignancies with the hyperimmunoglobulin E syndrome: a 19-year-old patient with Hodgkin disease and a 10-year-old with a fatal histiocytic lymphoma of the brain (14,15). ACKNOWLEDGMENT We acknowledge with thanks the support of Westwood Pharmaceuticals in underwriting the cost of color illustrations for this section of the journal. John G. Roth, M.D., Timothy L. Parker, M.D., and Nancy B. Esterly, M.D.* Departments of Dermatology and "'Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin REFERENCES 1. Leung DYM, Geha RS. Clinical and immunologic aspects of hyperimmunoglobulin E syndrome, Hematol Oncol Clin North Am 1988;2:81-10!. 2. Buckley RH, Wray BB, Belmaker EZ, Extreme hyperimmunoglobulin E and undue susceptibility to infection. Pediatrics i972;49:59-67. 3. Dreskin S, Gallin J. Evolution of the hyperimmunoglobulin E and recurrent infection (HIE, Job's) syndrome in a young girl. J Allergy Clin Immunol 1987; 80:746-751, 4. Dongbedian H, Gallin J. The hyperimmunoglobulin E recurrent-infection (Job's) syndrome. A review of the NIH experience and the literature. Medicine 1983;62: 195-208. 5. Butrus SI, Leung DYM, Gellis S, et al. Vernal con-
The Syndrome Page
6.
7. 8.
9.
10.
junctivitis in the hyperimmunoglobulin E syndrome. Ophthalmology 1984;91:1213-1216. Hochreutener H, Wuthrich B, Huwyler T, et al. Variant of hyper-lgE syndrome: the differential from atopic dermatitis is important because of treatment and prognosis. Dermatologica 1991;182:6-11. Buckley RH, Becker WG. Abnormalities in the regulation of human IgE synthesis. Immunol Rev 1978;41: 288-296. Dreskin S, Goldsmith P, Strober W, et al. Metabolism of immunoglobulin E in patients with markedly elevated serum immunoglobulin E levels. J Clin Invest 1972;79:1764-1772. Leung D, Ambrosino DM, Arbeit RD, et al. Impaired antibody response in the hyperimmunoglobulin E syndrome. J Allergy Clin Immunol 1988,81:1082!087. Hill HR, Quie PG, Pabst HF, et al. Defect in neutrophil granuiocyte chemotaxis in Job's syndrome of re-
U.
12. 13. 14. 15.
413
current "cold" staphylococcal abscesses. Lancet 1974;2:617-629. Jeppson J, Jaffe H, HiU HR. Use of recombinant human interferon gamma to enhance neutropbil chemotactic response in Job syndrome of hyperimmunoglobulin E and recurrent infections. J Pediatr 1991; 118:383-385. Leung D, Wood N, Geha RS. Reversal of cellular abnormalities in the hyper-lgE syndrome following plasmapheresis. Clin Res 1985;33:161A. Shuttleworth D, Hott P, Mathews A. Hyperimmunoglobulin E syndrome: treatment with isotretinoin. Br J Dennatol 1988;119:93-99. Merten DF, Buckley RH, Pratt PC, et al. Hyperimmunoglobulin E syndrome: radiographic observations. Radiology I979;132:71-79. Bale JF Jr, Wilson JF, Hill HR. Fatal histiocytic lymphoma of tbe brain associated with byperimmunoglobulin E and recurrent infections. Cancer 1977,39: 2386-2394.
CALL FOR PAPERS The editors of the Syndrome Page welcome submission of your manuscripts for consideration. Please submit them in triplicate to: Susan B. Mallory, M.D., Department of Dermatology, St. Louis Children's Hospitai, 400 S. Kingshighway, St. Louis, MO 63110
Editors: Susan B. MaUory, M.D., and Bernice R. Krafchik, M.B., Ch.B., F.R.C.P.(C)
What Syndrome Is This?
J12 years. Note the alope-
Figure 1. The f
^. •••- / i \ V Address correspondence to John G. Roth, M.D., 177 Burt Road, Lexington, KY 40503.
410
Figure 3. Lichenified plaques on the hands.
The Syndrome Page 411
The Hyperimmunoglobulin E Syndrome In February 1991 he was hospitalized with worsening of his dermatitis, and a right comeal ulcer that progressed to perforation and required corneal transplant. In addition to severe dermatitis, physical examination revealed extensive alopecia and coarse facia! features (Figs. 2 and 3). Punched-out erosions were present in the groin and over large areas of the back and buttocks (Fig. 4). There was periungual inflammation with onychodystrophy of all nails. Laboratory data during this hospitalization included a white blood cell count of 15.8 K/|xl with 61% segments, 4% bands, 11% lymphocytes, 14% monocytes, and 8% eosinophils. Immunoglobulin levels were IgG 2090 mg/dl (normal 574-1484 mg/ dl), IgM 30 mg/dl (50-232 mg/dl), IgA 385 mg/dl (40212 mg/dl), and IgE 13,000 mg/dl (30-250 mg/dl). Complement values were C3 58 mg/dl (89-195 mg/ dl) and C4 41 mg/dl (10-40 mg/dl). A hepatitis profile was negative, as was a human immunodeficiency virus titer. Skin cultures grew S. aureus and herpes simplex vims type 1. An IgE antistaphylococcal antibody determination showed 41.7% binding (control serum 3.4% binding). On previous occasions a defect in neutrophil chemotaxis had been demonstrated.
Figure 4. Dermatitis and excoriations on the torso. A 12-year-old boy developed severe dermatitis at 1 month of age that required daiiy application of topical steroids, and antibiotics for secondary infection. At 8 months, and again at 11 months of age, he was hospitalized for failure to thrive, vomiting, and wheezing. At 18 months he was hospitalized with disseminated eczema herpeticum followed by Pseudomonas sepsis. He then developed necrotizing left temporal and cephalic vein thrombophlebitis requiring fasciotomy and scalp debridement with grafting. Additional medical problems during that hospitalization were Staphylococcus aureus sepsis, meningitis, and left middle cerebral artery arteritis. He subsequently had two episodes of pneomococcal pneumonia. Throughout this time he had a recalcitrant, intensely pruritic dermatitis requiring daily topical steroids and oral antihistamines, and continuous dicloxacillin therapy for infection (Fig. 1).
THE HYPERIMMUNOGLOBULIN E SYNDROME The hyperimmunoglobulin E syndrome is a rare disorder characterized by a markedly elevated serum IgE level, chronic dermatitis, intense pruritus, and recurrent serious infections. In 1966 two fairskioned, red-haired females were described with severe eczema, recurrent sinopulmonary infections, and staphylococcal abscesses. The authors suggested the term Job's syndrome for these patients because of the remarkable absence of inflammation in the abscesses, resembling the description in the Book of Job (I). In 1972 two male patients were reported with similar findings in addition to coarse facies, recurrent skin, long and joint abscesses, extremely high serum immunoglobulin levels, and positive immediate cutaneous hypersensitivity reactions to S. aureus and Candida albicans (2). Ntimerous subsequent reports have documented this syndrome in individuals of both sexes with a variety of hair colors and diverse racial backgrounds. Features common to these patients are extremely ele-
412 Pediatric Dennatoiogy VoL 9 No. 4 December 1992 vated serum IgE levels, recurrent bacterial, fungal, and viral infections, and chronic dermatitis (3). The hyperimmunoglobulin E syndrome has become the standard designation for this disorder. The ?tge of onset of dermatitis is quite variable, but the eruption often develops within the first six weeks of life (1). Diffuse cutaneous herpes simplex or varicella may occur early (4), but deep-seated bacterial infections are generally not a prominent problem until after 6 months of age. The major organism is usually S. aureus; however, other bacterial pathogens are Haemophilus influenzae, group A Streptococcus, Escherichia coli, and Pseudomonas. Cutaneous infections with nonbacterial organisms are quite common, the most frequent being C. aibicans. Later, recurrent frequent episodes of herpes simplex involving mucosal and cutaneous surfaces may be complicated by herpetic keratoconjunctivitis (5). The differential diagnosis includes severe atopic dermatitis and primary immunodeficiencies such as hypogammaglobulinemia, Wiscott-Aldrich syndrome, and DeGeorge syndrome. The most difficult differentiation is with severe atopic dermatitis (6,7). Staphylococcus aureus infections in atopic dermatitis tend to be superficial; however, in hyperimmunoglobulin E syndrome they are more serious and deep seated. Patients with hyperimmunoglobulin E syndrome have a coarse facies manifested as a broad nasal bridge, prominent nose, and irregularly proportioned cheeks and jaw. Those with both diseases can have very high serum IgE levels and eosinophilia. Additional clinical complications of the hyperimmunoglobulin E syndrome that are not usually found in atopic dermatitis are nonstaphylococcal infections, osteoporosis, vernal conjunctivitis, and pyoderma gangrenosum. The most common laboratory abnormalities in the hyperimmunoglobulin E syndrome are a markedly elevated serum IgE level and peripheral eosinophilia (1,8). Eosinophils can account for as much as 40% to 50% of the differential, with total counts as high as 6600 K/jil. Serum IgG, IgM, IgA, C3, and C4 levels are usually normal. The most important laboratory finding is IgE antibody directed against S. aureus (1). This test is relatively specific in confirming the diagnosis (1). Immunoglobulin antibody also can be directed against C. aibicans, but this finding is less specific. Serum from patients with this syndrome may contain IgG antibody against IgE, but this antibody is not unique to the hyperimmunoglobulin syndrome (9), and nor are the neutrophil chemotactic defects, which probably
are not due to a primary defect in the leukocyte (10). Management of patients with the hyperimmunoglobulin E syndrome is difficult. Topical steroids and histamines are used for the pruritus and dermatitis but are often ineffective. The most effective treatment for S. aureus infections is dicloxacillin (1). Levamisole, ascorbic acid, cimetidine, interferon gamma, and transfer factor all have been reported to improve neutrophil chemotaxis (5,11). Intravenous gammaglobulin and plasmapheresis have been helpful in managing patients with severe disease (12). Although the beneficial effects are of short duration, these modalities should be used for patients who have failed more conservative approaches. A single case report described successful treatment with isotretinoin (13). The long-term prognosis of this disease is not known. Monitoring and prompt treatment of bacterial infections improve the course of the disease. Two case reports associated malignancies with the hyperimmunoglobulin E syndrome: a 19-year-old patient with Hodgkin disease and a 10-year-old with a fatal histiocytic lymphoma of the brain (14,15). ACKNOWLEDGMENT We acknowledge with thanks the support of Westwood Pharmaceuticals in underwriting the cost of color illustrations for this section of the journal. John G. Roth, M.D., Timothy L. Parker, M.D., and Nancy B. Esterly, M.D.* Departments of Dermatology and "'Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin REFERENCES 1. Leung DYM, Geha RS. Clinical and immunologic aspects of hyperimmunoglobulin E syndrome, Hematol Oncol Clin North Am 1988;2:81-10!. 2. Buckley RH, Wray BB, Belmaker EZ, Extreme hyperimmunoglobulin E and undue susceptibility to infection. Pediatrics i972;49:59-67. 3. Dreskin S, Gallin J. Evolution of the hyperimmunoglobulin E and recurrent infection (HIE, Job's) syndrome in a young girl. J Allergy Clin Immunol 1987; 80:746-751, 4. Dongbedian H, Gallin J. The hyperimmunoglobulin E recurrent-infection (Job's) syndrome. A review of the NIH experience and the literature. Medicine 1983;62: 195-208. 5. Butrus SI, Leung DYM, Gellis S, et al. Vernal con-
The Syndrome Page
6.
7. 8.
9.
10.
junctivitis in the hyperimmunoglobulin E syndrome. Ophthalmology 1984;91:1213-1216. Hochreutener H, Wuthrich B, Huwyler T, et al. Variant of hyper-lgE syndrome: the differential from atopic dermatitis is important because of treatment and prognosis. Dermatologica 1991;182:6-11. Buckley RH, Becker WG. Abnormalities in the regulation of human IgE synthesis. Immunol Rev 1978;41: 288-296. Dreskin S, Goldsmith P, Strober W, et al. Metabolism of immunoglobulin E in patients with markedly elevated serum immunoglobulin E levels. J Clin Invest 1972;79:1764-1772. Leung D, Ambrosino DM, Arbeit RD, et al. Impaired antibody response in the hyperimmunoglobulin E syndrome. J Allergy Clin Immunol 1988,81:1082!087. Hill HR, Quie PG, Pabst HF, et al. Defect in neutrophil granuiocyte chemotaxis in Job's syndrome of re-
U.
12. 13. 14. 15.
413
current "cold" staphylococcal abscesses. Lancet 1974;2:617-629. Jeppson J, Jaffe H, HiU HR. Use of recombinant human interferon gamma to enhance neutropbil chemotactic response in Job syndrome of hyperimmunoglobulin E and recurrent infections. J Pediatr 1991; 118:383-385. Leung D, Wood N, Geha RS. Reversal of cellular abnormalities in the hyper-lgE syndrome following plasmapheresis. Clin Res 1985;33:161A. Shuttleworth D, Hott P, Mathews A. Hyperimmunoglobulin E syndrome: treatment with isotretinoin. Br J Dennatol 1988;119:93-99. Merten DF, Buckley RH, Pratt PC, et al. Hyperimmunoglobulin E syndrome: radiographic observations. Radiology I979;132:71-79. Bale JF Jr, Wilson JF, Hill HR. Fatal histiocytic lymphoma of tbe brain associated with byperimmunoglobulin E and recurrent infections. Cancer 1977,39: 2386-2394.
CALL FOR PAPERS The editors of the Syndrome Page welcome submission of your manuscripts for consideration. Please submit them in triplicate to: Susan B. Mallory, M.D., Department of Dermatology, St. Louis Children's Hospitai, 400 S. Kingshighway, St. Louis, MO 63110
