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B-cell lymphoma in a patient with WHIM syndrome
B-cell lymphoma in a patient with WHIM syndrome K. Mireille Chae, MD, James O. Ertle, MD, and Michael D. Tharp, MD Chicago, Illinois WHIM syndrome is a rare congenital familial syndrome consisting of warts, hypogammaglobulinemia, infections, and myelokathexis. We describe a 30-year-old man with WHIM syndrome, in whom red dermal facial nodules developed. The diagnosis of B-cell lymphoma was established with biopsy and immunohistochemical studies. To our knowledge, this is the first reported case of WHIM syndrome complicated by a B-cell lymphoma. (J Am Acad Dermatol 2001;44:124-8.)
W
HIM syndrome is an acronym for a congenital familial neutropenic disorder with the tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis.1 Myelokathexis is a rare chronic severe neutropenia that is characterized by bone marrow myeloid hyperplasia with a low peripheral leukocyte count. An increased incidence of lymphoma is seen in various types of immune deficiency disorders. To date, however, lymphoma has not been described in association with WHIM syndrome. We report a case of cutaneous B-cell lymphoma in a patient with WHIM syndrome.
CASE REPORT A 30-year-old white man with WHIM syndrome presented for evaluation of right-sided facial nodules that had been present for 1 year. The first lesion developed on the right cheek. Other lesions subsequently appeared along the right mandible and below the right ear. Accelerated growth of the lesion on the right cheek was noted during a 6-month period before presentation. There was no history of fevers, chills, and night sweats. The patient exhibited the full spectrum of WHIM syndrome with warts, hypogammaglobulinemia, recurrent bacterial infections, and severe leukopenia. Since childhood, the patient remembered hav-
From the Department of Dermatology, Rush-Presbyterian-St Luke’s Medical Center. Reprint requests: Michael D. Tharp, MD, Chairman, Department of Dermatology, Rush-Presbyterian-St Luke’s Medical Center, 1653 W Congress Pkwy, Chicago, IL 60612-3864. E-mail: mtharp@ rpslmc.edu. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/91/111337 doi:10.1067/mjd.2001.111337
124
ing warts on his hands and feet. He was hospitalized in 1992 and 1993 for a shoulder abscess and an abdominal abscess, respectively. He had otherwise been healthy over the past few years before development of the facial nodules. The patient’s family history was significant in that his mother, sister, brother, and one niece also have WHIM syndrome (Fig 1). On physical examination, a firm red plaque measuring 4.6 × 3.5 cm was evident on the right cheek (Fig 2, A). A red, smooth plaque measuring 0.8 cm in diameter was located below the larger nodule, and the right mandible contained a 1.8 × 2.0 cm firm plaque. A slightly raised, red plaque also could be palpated behind the right ear. No hepatosplenomegaly was evident on physical examination. Fullness in the right axillary region was noted. Biopsy specimens from the right cheek revealed a diffuse monomorphous infiltrate of atypical lymphocytes with sparing of the uppermost dermis (Fig 3). Immunohistochemical studies showed the majority of the lymphoid cells to be positive for the B-cell marker CD20. Scattered CD3+ T cells were present and CD30 stains were negative. B-cell clonality was documented by the presence of immunoglobulin heavy chain gene rearrangement. EpsteinBarr virus genome was detected in lesional skin by polymerase chain reaction. A bone marrow biopsy specimen revealed a hypercellular marrow with small lymphoid aggregates of large pleomorphic cells. Computed tomographic scans of the chest, abdomen, and pelvis demonstrated a mass in the right axilla and adenopathy of the right axillary, right hilar, and right inguinal areas. The spleen was slightly enlarged. Results of laboratory studies were normal except for neutropenia. The diagnosis of B-cell lymphoma was made, and the patient was referred to oncology who adminis-
Chae, Ertle, and Tharp 125
J AM ACAD DERMATOL VOLUME 44, NUMBER 1
Fig 1. Patient’s family history is significant for WHIM syndrome; mother, sister, brother, and niece were affected.
A
B
Fig 2. A, Facial nodules and plaques developed in the 12 months before therapy. B, Nodules and plaques resolved after 6 cycles of CHOP therapy.
tered 6 cycles of CHOP therapy (cytoxan, Adriamycin, vincristine, prednisone) over 18 weeks. Granulocyte colony-stimulating factor (G-CSF) was given before each cycle to increase the patient’s white blood cell count. After 2 cycles of chemotherapy, flattening of the facial nodules was evident. At the end of the sixth treatment, all of the nodules had resolved, leaving only a faint erythema (Fig 2, B).
Repeat computed tomographic scans also showed resolution of the axillary mass and adenopathy. The patient’s warts remained unchanged.
DISCUSSION The acronym WHIM was coined by Wetzler et al1 while describing a father and two daughters with a unique combination of chronic papillomavirus
126 Chae, Ertle, and Tharp
J AM ACAD DERMATOL JANUARY 2001
B
A
Fig 3. A, Low-power view shows diffuse infiltrate with sparing of the uppermost dermis. B, Higher power view shows atypical monomorphous lymphocytes. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×10; B, ×40.)
Table I. Reports of patients with WHIM syndrome Patient No.
Age*/Sex
Family history
1†
12 mo/F
(+)Father (patient 2)
2† 3†
31 y/M 23 y/F
(+)Daughter (patient 1) (+)Sister (patient 4) and father
4†
22 y/F
5
M father
6†
16 y/M
(+)Sister (patient 3) and father (+)2 daughters (patients 3, 4) (-)
7†
27 y/F
(+)Son
8 9
10 11† 12 13†
M
Additional findings
Yes Yes Yes
Yes
Neutrophils able to migrate into peripheral blood suggests normal function; increased infections may be secondary to defect in humoral immunity
Mentzer et al2 (pts 1 and 2)
Yes Yes Yes Yes Yes Yes
Yes Yes
“WHIM syndrome,” autosomal dominant or X-linked dominant; gammaglobulins decreased bacterial infections, but no effect on warts
Wetzler et al1,3 (pts 3, 4, and 5)
Yes Yes Yes
Yes
Yes NR Yes Yes Yes Yes
NR Yes
Yes Yes Yes
Yes
Recurrent infections reduced with intravenous gammaglobulin Summarized previous cases of myelokathexis; G-CSF and GM-CSF mobilize granulocytes from bone marrow as does infection, corticosteroids, and epinephrine
Goddard, Hughes, Beatty4 (pt 6) Hord et al5 (pts 7 and 8)
39 mo/M (+)Mother (patient 6) 40 y/F (+)Son
No NR
Yes Yes Yes Yes
Yes Yes
Depressed bcl-x expression in bone marrow–derived granulocyte precursor cells; bcl-x and absolute neutrophil count increase with G-CSF
Aprikyan et al6 (pts 9-12)
20 y/M 20 y/F 12 mo/F 30 y/M
NR Yes Yes Yes Yes Yes NR NR Yes Yes Yes Yes
Yes Yes Yes Yes
B-cell lymphoma
Current study
(+)Mother (+)Daughter (+)Mother (patient 7) (+)Mother, sister, niece
W
H
I
Authors
G-CSF, Granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; H, hypogammaglobulinemia; I, infections; M, myelokathexis/neutropenia; NR, not reported; W, warts. *Patient’s age at the time of report. †Patient with full spectrum of WHIM syndrome.
J AM ACAD DERMATOL VOLUME 44, NUMBER 1
infection of the skin, chronic bacterial sinopulmonary infections, low immunoglobulin levels, and peripheral neutropenia in the face of a hypercellular bone marrow. From this kindred, it was proposed that WHIM syndrome represented either an autosomal or X-linked dominant inheritance. To date, there have been 7 cases of WHIM syndrome (Table I).1-6 Patients with myelokathexis and WHIM syndrome typically present at ages ranging from 1 to 20 years with a history of recurrent febrile bacterial infections, such as pneumonia, sinusitis, adenitis, otitis media, urinary tract infections, and enteritis. Significant neutropenia is invariably found, except in the presence of infection when leukocytosis and neutrophilia can occur.7,8 No ethnic predilection is apparent, and both male and female patients are affected. Given the relative infrequency of Xlinked dominant conditions, it has been suggested that autosomal-dominant inheritance is more likely,9 and our patient’s family history further supports an autosomal dominant inheritance pattern for WHIM syndrome. Zuelzer7 first reported a rare form of severe congenital neutropenia and used the term myelokathexis (kathexis = retention) to describe the retention of mature neutrophils in a hyperplastic marrow. Additional patients have been characterized with severe noncyclic neutropenia, recurrent infections, and granulocytic hyperplasia of the bone marrow with degenerative changes in mature neutrophils.1,2,5,8-16 The mechanism for myelokathexis appears to result from accelerated apoptosis of neutrophils in the bone marrow.1,17 More recently, a selective decrease in bcl-x expression has been demonstrated in the myeloid precursors of 4 patients with myelokathexis.6 Bcl-x is an important regulator of hematopoietic cell growth and is considered an antiapoptotic factor. With the use of immunohistochemical analysis, a selective decrease in bcl-x expression has been observed in the myeloid precursors of patients with myelokathexis. Treatment of patients with myelokathexis with GCSF increases bcl-x expression, thereby reducing neutrophil apoptosis and leading to an increased peripheral blood neutrophil count.6 Our patient had a beneficial response to G-CSF, with an increase in his white blood cell count from 0.587 × 103/µL to 4 × 103/µL. The pathogenesis of the hypogammaglobulinemia in WHIM syndrome presently is unknown; however, Mentzer et al2 and Goddard, Hughes, and Beatty4 reported a reduction in the frequency of infections with monthly gammaglobulin therapy in their patients with WHIM syndrome. The association of malignancy with different types of disorders is
Chae, Ertle, and Tharp 127
well established and believed to result from defective immune surveillance.18-20 For example, the risk of lymphoma is increased in patients with various congenital immune deficiency disorders, such as Wiskott-Aldrich syndrome and ataxia-telangiectasia.18 We believe that our patient’s overall state of immunosuppression left him vulnerable to EpsteinBarr virus infection and the subsequent development of a B-cell lymphoma. Thus our case report represents the eighth patient with WHIM syndrome and, to our knowledge, the first complicated by a Bcell lymphoma. REFERENCES 1. Wetzler M, Talpaz M, Kleinerman ES, King A, Huh YO, Gutterman JU, et al. A new familial immunodeficiency disorder characterized by severe neutropenia, a defective marrow release mechanism, and hypogammaglobulinemia. Am J Med 1990;89:66372. 2. Mentzer WC, Johnston RB, Baehner RL, Nathan DG. An unusual form of chronic neutropenia in a father and daughter with hypogammaglobulinaemia. Br J Haematol 1977;36:313-22. 3. Wetzler M, Talpaz M, Kellagher MJ, Gutterman JU, Kurzrock R. Myelokathexis: normalization of neutrophil counts and morphology by GM-CSF. JAMA 1992;267:2179-80. 4. Goddard EA, Hughes EJ, Beatty DW. A case of immunodeficiency characterized by neutropenia, hypogammaglobulinemia, recurrent infections and warts. Clin Lab Haematol 1994;16:297302. 5. Hord JD, Whitlock JA, Gay JC, Lukens JN. Clinical features of myelokathexis and treatment with hematopoietic cytokines: a case report of two patients and a review of the literature. J Pediatr Hematol Oncol 1997;19:443-8. 6. Aprikyan AAG, Liles WC, Park JR, Jonas M, Chi EY, Dale DC. Myelokathexis, a congenital disorder of severe neutropenia characterized by accelerated apoptosis and defective expression of bcl-x in neutrophil precursors. Blood 2000;95:320-7. 7. Zuelzer WW.“Myelokathexis”—a new form of chronic granulocytopenia: report of a case. N Engl J Med 1964;270:699-704. 8. Krill CE, Smith HD, Mauer AM. Chronic idiopathic granulocytopenia. N Engl J Med 1964;270:973-9. 9. Christ MJ, Dillon CA. Myelokathexis in a mother and infant: a second case suggesting dominant inheritance. Mil Med 1997; 162:827-8. 10. O’Regan S, Newman AJ, Graham RC.‘Myelokathexis’: neutropenia with marrow hyperplasia. Am J Dis Child 1977;131:655-8. 11. Bohinjec J. Myelokathexis: chronic neutropenia with hyperplastic bone marrow with hypersegmented neutrophils in two siblings. Blut 1981;42:191-6. 12. Bohinjec J, Andoljsek D. Neutrophil-releasing activity of recombinant human granulocyte-macrophage colony stimulating factor in myelokathexis. Br J Haematol 1992;82:169-72. 13. Bassan R,Viero P, Minetti B, Comotti B, Barbui T. Myelokathexis: a rare form of chronic benign granulocytopenia. Br J Haematol 1984;58:115-7. 14. Plebani A, Cantu-Rajnoldi A, Collow G, Allavena P, Biolchini A, Pirelli A, et al. Myelokathexis associated with multiple congenital malformations: immunological study on phagocytic cells and lymphocytes. Eur J Haematol 1988;40:12-7. 15. Weston B, Axtell RA, Todd RF, Vincent M, Balazovich KJ, Suchard SJ, et al. Clinical and biologic effects of granulocyte colony stimulating factor in the treatment of myelokathexis. J Pediatr 1991; 118:229-34.
128 Chae, Ertle, and Tharp
16. Hess U, Ganser A, Schnürch HG, Seipelt G, Ottman OG, Falk S, et al. Myelokathexis treated with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Br J Haematol 1992;80:254-6. 17. Taniuchi S, Yamamoto A, Fujiwara T, Hasui M, Tsuji S, Kobayashi Y. Dizygotic twin sisters with myelokathexis: mechanism of its neutropenia. Am J Hematol 1999;62:106-11.
J AM ACAD DERMATOL JANUARY 2001
18. Filipovich AH, Spector BD, Kersey J. Immunodeficiency in humans as a risk factor in the development of malignancy. Prev Med 1980;9:252-9. 19. Levine AM. Lymphoma complicating immunodeficiency disorders. Ann Oncol 1994;5(Suppl):S29-S35. 20. Penn I. The role of immunosuppression in lymphoma formation. Semin Immunopathol 1998;20:343-55.
W
HIM syndrome is an acronym for a congenital familial neutropenic disorder with the tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis.1 Myelokathexis is a rare chronic severe neutropenia that is characterized by bone marrow myeloid hyperplasia with a low peripheral leukocyte count. An increased incidence of lymphoma is seen in various types of immune deficiency disorders. To date, however, lymphoma has not been described in association with WHIM syndrome. We report a case of cutaneous B-cell lymphoma in a patient with WHIM syndrome.
CASE REPORT A 30-year-old white man with WHIM syndrome presented for evaluation of right-sided facial nodules that had been present for 1 year. The first lesion developed on the right cheek. Other lesions subsequently appeared along the right mandible and below the right ear. Accelerated growth of the lesion on the right cheek was noted during a 6-month period before presentation. There was no history of fevers, chills, and night sweats. The patient exhibited the full spectrum of WHIM syndrome with warts, hypogammaglobulinemia, recurrent bacterial infections, and severe leukopenia. Since childhood, the patient remembered hav-
From the Department of Dermatology, Rush-Presbyterian-St Luke’s Medical Center. Reprint requests: Michael D. Tharp, MD, Chairman, Department of Dermatology, Rush-Presbyterian-St Luke’s Medical Center, 1653 W Congress Pkwy, Chicago, IL 60612-3864. E-mail: mtharp@ rpslmc.edu. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/91/111337 doi:10.1067/mjd.2001.111337
124
ing warts on his hands and feet. He was hospitalized in 1992 and 1993 for a shoulder abscess and an abdominal abscess, respectively. He had otherwise been healthy over the past few years before development of the facial nodules. The patient’s family history was significant in that his mother, sister, brother, and one niece also have WHIM syndrome (Fig 1). On physical examination, a firm red plaque measuring 4.6 × 3.5 cm was evident on the right cheek (Fig 2, A). A red, smooth plaque measuring 0.8 cm in diameter was located below the larger nodule, and the right mandible contained a 1.8 × 2.0 cm firm plaque. A slightly raised, red plaque also could be palpated behind the right ear. No hepatosplenomegaly was evident on physical examination. Fullness in the right axillary region was noted. Biopsy specimens from the right cheek revealed a diffuse monomorphous infiltrate of atypical lymphocytes with sparing of the uppermost dermis (Fig 3). Immunohistochemical studies showed the majority of the lymphoid cells to be positive for the B-cell marker CD20. Scattered CD3+ T cells were present and CD30 stains were negative. B-cell clonality was documented by the presence of immunoglobulin heavy chain gene rearrangement. EpsteinBarr virus genome was detected in lesional skin by polymerase chain reaction. A bone marrow biopsy specimen revealed a hypercellular marrow with small lymphoid aggregates of large pleomorphic cells. Computed tomographic scans of the chest, abdomen, and pelvis demonstrated a mass in the right axilla and adenopathy of the right axillary, right hilar, and right inguinal areas. The spleen was slightly enlarged. Results of laboratory studies were normal except for neutropenia. The diagnosis of B-cell lymphoma was made, and the patient was referred to oncology who adminis-
Chae, Ertle, and Tharp 125
J AM ACAD DERMATOL VOLUME 44, NUMBER 1
Fig 1. Patient’s family history is significant for WHIM syndrome; mother, sister, brother, and niece were affected.
A
B
Fig 2. A, Facial nodules and plaques developed in the 12 months before therapy. B, Nodules and plaques resolved after 6 cycles of CHOP therapy.
tered 6 cycles of CHOP therapy (cytoxan, Adriamycin, vincristine, prednisone) over 18 weeks. Granulocyte colony-stimulating factor (G-CSF) was given before each cycle to increase the patient’s white blood cell count. After 2 cycles of chemotherapy, flattening of the facial nodules was evident. At the end of the sixth treatment, all of the nodules had resolved, leaving only a faint erythema (Fig 2, B).
Repeat computed tomographic scans also showed resolution of the axillary mass and adenopathy. The patient’s warts remained unchanged.
DISCUSSION The acronym WHIM was coined by Wetzler et al1 while describing a father and two daughters with a unique combination of chronic papillomavirus
126 Chae, Ertle, and Tharp
J AM ACAD DERMATOL JANUARY 2001
B
A
Fig 3. A, Low-power view shows diffuse infiltrate with sparing of the uppermost dermis. B, Higher power view shows atypical monomorphous lymphocytes. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×10; B, ×40.)
Table I. Reports of patients with WHIM syndrome Patient No.
Age*/Sex
Family history
1†
12 mo/F
(+)Father (patient 2)
2† 3†
31 y/M 23 y/F
(+)Daughter (patient 1) (+)Sister (patient 4) and father
4†
22 y/F
5
M father
6†
16 y/M
(+)Sister (patient 3) and father (+)2 daughters (patients 3, 4) (-)
7†
27 y/F
(+)Son
8 9
10 11† 12 13†
M
Additional findings
Yes Yes Yes
Yes
Neutrophils able to migrate into peripheral blood suggests normal function; increased infections may be secondary to defect in humoral immunity
Mentzer et al2 (pts 1 and 2)
Yes Yes Yes Yes Yes Yes
Yes Yes
“WHIM syndrome,” autosomal dominant or X-linked dominant; gammaglobulins decreased bacterial infections, but no effect on warts
Wetzler et al1,3 (pts 3, 4, and 5)
Yes Yes Yes
Yes
Yes NR Yes Yes Yes Yes
NR Yes
Yes Yes Yes
Yes
Recurrent infections reduced with intravenous gammaglobulin Summarized previous cases of myelokathexis; G-CSF and GM-CSF mobilize granulocytes from bone marrow as does infection, corticosteroids, and epinephrine
Goddard, Hughes, Beatty4 (pt 6) Hord et al5 (pts 7 and 8)
39 mo/M (+)Mother (patient 6) 40 y/F (+)Son
No NR
Yes Yes Yes Yes
Yes Yes
Depressed bcl-x expression in bone marrow–derived granulocyte precursor cells; bcl-x and absolute neutrophil count increase with G-CSF
Aprikyan et al6 (pts 9-12)
20 y/M 20 y/F 12 mo/F 30 y/M
NR Yes Yes Yes Yes Yes NR NR Yes Yes Yes Yes
Yes Yes Yes Yes
B-cell lymphoma
Current study
(+)Mother (+)Daughter (+)Mother (patient 7) (+)Mother, sister, niece
W
H
I
Authors
G-CSF, Granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; H, hypogammaglobulinemia; I, infections; M, myelokathexis/neutropenia; NR, not reported; W, warts. *Patient’s age at the time of report. †Patient with full spectrum of WHIM syndrome.
J AM ACAD DERMATOL VOLUME 44, NUMBER 1
infection of the skin, chronic bacterial sinopulmonary infections, low immunoglobulin levels, and peripheral neutropenia in the face of a hypercellular bone marrow. From this kindred, it was proposed that WHIM syndrome represented either an autosomal or X-linked dominant inheritance. To date, there have been 7 cases of WHIM syndrome (Table I).1-6 Patients with myelokathexis and WHIM syndrome typically present at ages ranging from 1 to 20 years with a history of recurrent febrile bacterial infections, such as pneumonia, sinusitis, adenitis, otitis media, urinary tract infections, and enteritis. Significant neutropenia is invariably found, except in the presence of infection when leukocytosis and neutrophilia can occur.7,8 No ethnic predilection is apparent, and both male and female patients are affected. Given the relative infrequency of Xlinked dominant conditions, it has been suggested that autosomal-dominant inheritance is more likely,9 and our patient’s family history further supports an autosomal dominant inheritance pattern for WHIM syndrome. Zuelzer7 first reported a rare form of severe congenital neutropenia and used the term myelokathexis (kathexis = retention) to describe the retention of mature neutrophils in a hyperplastic marrow. Additional patients have been characterized with severe noncyclic neutropenia, recurrent infections, and granulocytic hyperplasia of the bone marrow with degenerative changes in mature neutrophils.1,2,5,8-16 The mechanism for myelokathexis appears to result from accelerated apoptosis of neutrophils in the bone marrow.1,17 More recently, a selective decrease in bcl-x expression has been demonstrated in the myeloid precursors of 4 patients with myelokathexis.6 Bcl-x is an important regulator of hematopoietic cell growth and is considered an antiapoptotic factor. With the use of immunohistochemical analysis, a selective decrease in bcl-x expression has been observed in the myeloid precursors of patients with myelokathexis. Treatment of patients with myelokathexis with GCSF increases bcl-x expression, thereby reducing neutrophil apoptosis and leading to an increased peripheral blood neutrophil count.6 Our patient had a beneficial response to G-CSF, with an increase in his white blood cell count from 0.587 × 103/µL to 4 × 103/µL. The pathogenesis of the hypogammaglobulinemia in WHIM syndrome presently is unknown; however, Mentzer et al2 and Goddard, Hughes, and Beatty4 reported a reduction in the frequency of infections with monthly gammaglobulin therapy in their patients with WHIM syndrome. The association of malignancy with different types of disorders is
Chae, Ertle, and Tharp 127
well established and believed to result from defective immune surveillance.18-20 For example, the risk of lymphoma is increased in patients with various congenital immune deficiency disorders, such as Wiskott-Aldrich syndrome and ataxia-telangiectasia.18 We believe that our patient’s overall state of immunosuppression left him vulnerable to EpsteinBarr virus infection and the subsequent development of a B-cell lymphoma. Thus our case report represents the eighth patient with WHIM syndrome and, to our knowledge, the first complicated by a Bcell lymphoma. REFERENCES 1. Wetzler M, Talpaz M, Kleinerman ES, King A, Huh YO, Gutterman JU, et al. A new familial immunodeficiency disorder characterized by severe neutropenia, a defective marrow release mechanism, and hypogammaglobulinemia. Am J Med 1990;89:66372. 2. Mentzer WC, Johnston RB, Baehner RL, Nathan DG. An unusual form of chronic neutropenia in a father and daughter with hypogammaglobulinaemia. Br J Haematol 1977;36:313-22. 3. Wetzler M, Talpaz M, Kellagher MJ, Gutterman JU, Kurzrock R. Myelokathexis: normalization of neutrophil counts and morphology by GM-CSF. JAMA 1992;267:2179-80. 4. Goddard EA, Hughes EJ, Beatty DW. A case of immunodeficiency characterized by neutropenia, hypogammaglobulinemia, recurrent infections and warts. Clin Lab Haematol 1994;16:297302. 5. Hord JD, Whitlock JA, Gay JC, Lukens JN. Clinical features of myelokathexis and treatment with hematopoietic cytokines: a case report of two patients and a review of the literature. J Pediatr Hematol Oncol 1997;19:443-8. 6. Aprikyan AAG, Liles WC, Park JR, Jonas M, Chi EY, Dale DC. Myelokathexis, a congenital disorder of severe neutropenia characterized by accelerated apoptosis and defective expression of bcl-x in neutrophil precursors. Blood 2000;95:320-7. 7. Zuelzer WW.“Myelokathexis”—a new form of chronic granulocytopenia: report of a case. N Engl J Med 1964;270:699-704. 8. Krill CE, Smith HD, Mauer AM. Chronic idiopathic granulocytopenia. N Engl J Med 1964;270:973-9. 9. Christ MJ, Dillon CA. Myelokathexis in a mother and infant: a second case suggesting dominant inheritance. Mil Med 1997; 162:827-8. 10. O’Regan S, Newman AJ, Graham RC.‘Myelokathexis’: neutropenia with marrow hyperplasia. Am J Dis Child 1977;131:655-8. 11. Bohinjec J. Myelokathexis: chronic neutropenia with hyperplastic bone marrow with hypersegmented neutrophils in two siblings. Blut 1981;42:191-6. 12. Bohinjec J, Andoljsek D. Neutrophil-releasing activity of recombinant human granulocyte-macrophage colony stimulating factor in myelokathexis. Br J Haematol 1992;82:169-72. 13. Bassan R,Viero P, Minetti B, Comotti B, Barbui T. Myelokathexis: a rare form of chronic benign granulocytopenia. Br J Haematol 1984;58:115-7. 14. Plebani A, Cantu-Rajnoldi A, Collow G, Allavena P, Biolchini A, Pirelli A, et al. Myelokathexis associated with multiple congenital malformations: immunological study on phagocytic cells and lymphocytes. Eur J Haematol 1988;40:12-7. 15. Weston B, Axtell RA, Todd RF, Vincent M, Balazovich KJ, Suchard SJ, et al. Clinical and biologic effects of granulocyte colony stimulating factor in the treatment of myelokathexis. J Pediatr 1991; 118:229-34.
128 Chae, Ertle, and Tharp
16. Hess U, Ganser A, Schnürch HG, Seipelt G, Ottman OG, Falk S, et al. Myelokathexis treated with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Br J Haematol 1992;80:254-6. 17. Taniuchi S, Yamamoto A, Fujiwara T, Hasui M, Tsuji S, Kobayashi Y. Dizygotic twin sisters with myelokathexis: mechanism of its neutropenia. Am J Hematol 1999;62:106-11.
J AM ACAD DERMATOL JANUARY 2001
18. Filipovich AH, Spector BD, Kersey J. Immunodeficiency in humans as a risk factor in the development of malignancy. Prev Med 1980;9:252-9. 19. Levine AM. Lymphoma complicating immunodeficiency disorders. Ann Oncol 1994;5(Suppl):S29-S35. 20. Penn I. The role of immunosuppression in lymphoma formation. Semin Immunopathol 1998;20:343-55.