A seven-month-old infant with fever and neutrophilic leukocytosis

CLINICAL CONFERENCE

A seven-month-old infant with fever and neutrophilic leukocytosis Julie D. Fishbein, MD, Carol S. Bruggers, MD, N o a h J. Friedman, MD,* M i c h a e l L. G r a h a m , MD, a n d J o a n n e Kurtzberg, MD From the Divisions of Hematology/Oncology and Immunology, Duke University Medical Center, Durham, North Carolina CASE PRESENTATION DR. FISHBEIN: A 7-month-old Lumbee Indian infant was admitted to Duke University Medical Center for evaluation of fever and leukocytosis. The infant's neonatal history was significant for bradycardia and cyanosis at birth, requiring resuscitation and transfer to the neonatal intensive care unit. Evaluation revealed group B streptococcal sepsis by urine counterimmunoelectrophoresis, although cultures of blood, urine, and spinal fluid were negative for these organisms. The infant remained in the hospital for 17 days, with recurrent fever and persistent leukocytosis (19,700 cells/ mm 3 at birth to 47,700 cells/mm3 at the time of discharge). The patient was examined at 3 months of age for a persistent umbilical granuloma. Elective excision was scheduled, but the patient was admitted on an emergency basis, on the day before surgery, for fever and omphalitis. A Gram stain of the umbilical discharge showed no polymorphonuclear ceils. A culture grew Enterococcus and Klebsiella pneumoniae. Blood cultures were negative for these organisms. The patient was treated in the hospital with parenterally administered antibiotics for 5 days. During that hospital stay the leukocyte count ranged from 67,000 cells/ mm 3 on admission to 42,000 cells/mm 3 at discharge. The patient did not return for follow-up appointments. At the age of 6 months the patient was seen at a hematology clinic for evaluation of persistent leukocytosis and six episodes of otitis media. Leukemoid reaction and iron deft-

Supported in part by National Institute of Health grants 5T32CA09307 and T32AI07062. Dr. Kurtzberg is a Scholar of the Leukemia Society of America. Submitted for publication Sept. 5, 1991; accepted Oct. 21, 1991. Reprint requests: Julie D. Fishbein, MD, Pediatric Hematology/ Oncology, Box 2916, Duke University Medical Center, Durham, NC 27710. *Now with the Southern California Permanente Medical Group, San Diego, Calif. 9/32/34486

ciency anemia were diagnosed, and iron supplementation was prescribed. She was again lost to follow-up. The patient was seen in a local emergency department on the day of admission with a 1-week history of mild, intermittent cough, fever, and diminished appetite. The leukocyte count was 83,900 ceUs/mm 3 with 82% neutrophils. She was transferred to Duke University MedicaI Center for evaluation. The patient's growth and development were normal. She had received two diphtheria-tetanus-pertussis immunizations and two live polio immunizations with no untoward effects. She was taking cefaclor twice daily for otitis media at the time of admission. The family history was not contributory. There were no infant deaths, no known consanCGD HIV LAD LFA- 1 NADPH NK

Chronic granulomatous disease Human immunodeficiencyvirus Leukocyte adhesiondeficiency Leukocyte function-associated antigen type 1 Nicotinamide-adenine dinucleotide phosphate (reduced form) Natural killer [cell]

guinity, and no known tuberculosis exposure. The patient had no siblings. When the infant was admitted to the hospital, her temperature was 36.8 ~ C, pulse rate 160 heats/min, respirations 44 breaths/min, and blood pressure 113/50 mm Hg. Height was 66.5 cm (25th percentile), weight 6.29 kg (5th percentile), and head circumference 43 cm (50th percentile). The patient was a bright, well-hydrated, edentulous infant 'without dysmorphic features. Abdominal examination revealed a 2 cm umbilical hernia that was easily reducible and nontender. The findings were otherwise unremarkable. Hematocrit was 35%, mean corpuscular volume 66 fl, and reticulocyte count 16,000 cells//4 (normal range 20 to 120); hypochromia, microcyt0sis, and anisocytosis were noted on a peripheral-blood film. No Howell-Jolly bodies were seen. The platelet count was 588,000 cells/ram3. The

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Table I. Summary Of patient's blood Cell counts and manual differential cell counts

Segmented Band Hospital Hemoglobin Platelets Leukocytes neutrophils forms Lymphocytes Monocytes Eosinophils Hematocrit (1000/mm 3) (lO00/mm 3) (%) (%) (%) (%) (%) day (gm/di) 1 1 2 3 4 5 6 7 8 11

9.0 10.6 8.0 7.7 7.1 6.4 7.5 7.3 7.2 7.3

28.4 35.9 29 26 24 25 26 29 27 25

893 588 642 698 541 692 801 514 844 824

83.9 69.5 64.8 66.7 75.5 68.3 75.2 82.7 85 63.1

leukocyte count was 69,500 cells/mm 3, with 63% neutrophils, 24% lymphocytes. 10% monocytes, 1% eosinophils. and 2% atypical lymphocytes (Table I). Morphologic features of the neutrophil were significant only for increased numbers of vacuoles per cell No D6hle bodies or toxic granulations were present. Samples of blood, bone marrow, urine, and cerebrospinal fluid were cultured for bacterial, fungal, viral, and mycobacterial organisms to detect infectious disease. Results of urine and cerebrospinal fluid latex agglutination tests were negative for Streptococcus pneumomae, Haemophilus influenzae, .Neisseria meningitidis, and grou p B streptococci. Cryptococcal antigen and acid-fast. India ink, and Gram stains of cerebrospinal fluid were negative. Stool contained no leukocytes, ova, or parasites. Serum titers were negative for herpes simplex virus, cytomegalovirus, human immunodeficiency virus, rubella virus, and the protozoon Toxoplasma. The patient was nonreactive to both a 1:100 Candida skin test and a standard purified protein derivative test. Immunologic studies included the following results: serum IgG 1100 mg/dl (tSange 268 to 717); IgA 260 mg/dl (range 27 to 73); IgM 100 mg/dl (range 12 to 124); IgD 0.12 mg/dl (range 0.8 to 48); IgE 330 units/ml (range 1 to 222); tetanus antibody titer 1:2187 (low); diphtheria antibody titer 1:243 (low); fluorescent antinuclear antibody not detectable: whole hemolytic complement normal: and antiD N A antibody not detectable. Results of a nitroblue tetrazolium dye reduction test were normal. Other normal results included the following: peripheral lymphocyte karyotype; serum electrolyte, uric acid, and creatinine levels; liver aminotransferase activities; urinalysis findings; spot urinary vanillylmandelic acid level; hemoglobin electrophoresis findings; and free erythrocytic protoporphyrin concentration. A chest radiograph revealed minimal right basilar subsegmental atelectasis and a normal cardiac silhouette. Ra-

82 63 56 69

0 0 4 2

11 26 28 19

7 10 8 10

0 1 4 0

70

1

27

6

1

74

3

15

7

1

60

2

34

3

1

diologic studies, including bone scan, cranial computed tomography, gallium scan, liver:spleen and renal ultrasonography, and ech0cardi0graphy, showed no abnormalities. Bone marrow aspirate and biopsy revealed an overall cellularity of 100%, normal megakaryocyte morphologic characteristics and number, and a myeloid/erythroid ratio of 5:1 (elevated) with normal morphologic features and maturation. No malignant cells, granulomas, or increased numbers o f lymphocytes were seen. Stainable iron was present. Bone marrow cytogenetic analysis showed no abnormalities. On the second hospital day the patient had a temperature of 39.2 ~ C. She continued tO have daily fevers (temperatures of 38.2 ~ C to 39.3 ~ C), associated with irritability and with poor oral intake that necessitated intravenous hydration. Five sets of specimens for aerobic and anaerobic blood cultures and urine cultures were obtaine d. Urinalysis results were unremarkable. No leukocytes were seen. Culture of a clean-catch urine specimen obtained at admission grew > 100,000 Colonies/ml of both Escherichia coli and an Enterococcus species. Additional cultures before antibiotic administration grew < 100,000 colonies/ml of a gram-negative rodl On the seventh hospital day a 1 X 1 cm tender, nondraining, erythematous lesion developed at the bone marrow biopsy site. Culture specimens were obtained by needle aspiration, and treatment with nafcillin was begun but without appreciable improvement. TWO days later a culture of a specimen from the site gre w E. coli, which was susceptible to sulfamethoxazole and cefazolin. Sulfamethoxazoletrimethroprim therapy was begun. The cellulitis improved gradually, and other clinical symptoms resolved. A diagnostic procedure was performed. CLINICAL

DISCUSSION

DR. FISHBEIN: The prominent features of this patient's brief but intriguing history can be summarized as follows:

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1. Leukocytosis out of proportion to the degree of symptoms 2. Persistent and marked neutrophilia, without immature myeloid elements seen on peripheral-blood film 3. Recurrent infections, responsive to antibiotic therapy 4. Two unusual types of inflammation: cellulitis caused by an enteric organism at the site of bone marrow biopsy, and omphalitis Despite the myriad causes of neutrophilia listed by Nathan and Oski ~ (Table II), the plausible diagnostic considerations are few. Neutrophilia, defined as an increase in circulating neutrophils to greater than normal (7500 ceils/ mm3), can occur by three mechanisms. In the vast majority of pathologic states, neutrophilia is caused by release of neutrophil stores from the bone marrow and vascular endothelium; neutrophilia associated with infection, anesthesia, and hypoxia are common examples. The second mechanism entails a quickened pace of differentiation from myeloid precursor to mature neutrophil, as in certain neoplasms and, more recently, the therapeutic administration of recombinant growth factors. The third state involves delayed egress of neutrophils from the microcirculation into the tissues. Because of abnormalities of neutrophil chemotaxis, adhesion, or diapedesis, neutrophil migration into normal tissues and sites of infection or inflammation is prevented. Although leukemia is an important diagnostic consideration in a child with a leukocyte count on the order of 80,000 cells/mm 3, the absence of immature myeloid or lymphoid forms in peripheral blood negates all but chronic neutrophilic leukemia. This rare myeloproliferative disorder, described by Touhy 2 in 1920, is characterized by the constellation of an increased number of mature neutrophils, elevated leukocyte alkaline phosphatase activity, absence of the Philadelphia chromosome in marrow cells, lack of evidence of an underlying cause of a leukemoid reaction, hepatosplenomegaly, hyperuricemia, and elevated serum vitamin B12 levels.3 Diagnosis is confirmed by evidence of organ infiltration by mature neutrophils. This patient did not meet the criteria for chronic neutrophilic leukemia (leukocyte alkaline phosphatase activity was not determined). Other neoplastic disorders associated with neutrophilia, such as chronic myelogenous leukemia, juvenile chronic myelogenous leukemia, neuroblastoma, Hodgkin lymphoma, and various carcinomas, 4 are unlikely because of normal findings on bone marrow, radiologic, and physical examination, and normal urinary catecholamine values. Although occult infection can cause impressive leukocytosis, a thorough search in our patient yielded negative resuits. This search focused on bacterial infections that might explain a leukemoid reaction of this magnitude, such as osteomyelitis, abscess, mastoiditis, or pyelonephritis. Suba-

Infant with fever and neutrophilic leukocytosis

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T a b l e II. Disorders associated with neutrophilia

1. Increased neutrophilic granulopoiesis a. Hereditary neutrophilia b. Chronic idiopathic neutrophilia (1) Asplenia c. Neutrophilic leukemoid reactions (1) Inflammation, infection (2) Tumors (3) Drugs (e.g., glucocorticoids, lithium) (4) Postneutropenia rebound (5) Myeloproliferative disorders 2. Decreased neutrophil circulatory egress a. Drugs (glucocorticoids) b. Congenital disorders of neutrophil motility (e.g., actin dysfunction, glycoprotein-138 deficiency) 3. Diminished marginal pool shift a. Acute disorder (e.g., stress, intoxication, infection) b. Exercise c. Epinephrine 4. Increased release of neutrophils from marrow storage a. Drugs (e.g., endotoxin, glucocorticoids) b. Acute disorders (e.g., anesthesia, electric shock, abrupt change in temperature, emotional agitation, presence of C3e complement receptor, infections, hypoxia) From Nathan DG, Oski FA. Hematologyof infancyand childhood.3rd ed. Philadelphia:WB Saunders, 1987:810.

cute bacterial endocarditis, which may escape detection on an echocardiogram (sensitivity of 35 % to 100%), is unlikely given the lack of physical evidence and five blood cultures negative for common pathogens. The remaining possibilities include more uncommon pathogens, such as those causing tuberculosis, brucellosis, or leptospirosis. The history of recurrent infections and elevated serum immunoglobulin concentrations raises the possibility of human immunodeficiency virus infection. Negative HIV titers in this infant may be misleading, because the ability to make functional antibody may be impaired. For this reason, specimens for HIV culture should be obtained, HIV antigen measured, or maternal HIV titers performed. In this case, HIV was not detected in the patient's mother. Hereditary neutrophilia, hepatosplenomegaly, and thickened calvaria without increased susceptibility to infection occurred in three members of one family. 5 A fourth family member had recurrent otitis media, upper respiratory tract infections, gastroenteritis, chalazions, and mumps. Other causes of inherited neutropenia include trisomy 21 syndrome and ring (22) syndrome, a rare chromosomal anomaly that is manifested by mental retardation and facial deformities. 6 A normal appearance does not exclude the possibility of trisomy 21 mosaicism, 7 but leukemoid reactions described in patients with trisomy 21 include a variety

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Fishbein et al.

of transient myeloproliferative diseases, all of which are marked by immature leukocyte forms in the peripheral blood. Immunologic and granulocytic changes in children with trisomy 21 increase their susceptibility to infection, especially during the first year of life. The only consistent finding to account for this is a decreased responsiveness to the T-cell mitogen phytohemagglutinin. 8 Immature myeloid forms were conspicuously absent on repeated peripheral-blood films of our patient, making this diagnosis unlikely. Rheumatologic diagnoses that should be entertained include systemic juvenile rheumatoid arthritis, which is occasionally associated with leukocytosis (60,000 to 80,000 cells/ram3). This infant's physical examination findings were not consistent with the diagnosis of systemic-onset rheumatoid arthritis, given the notable absence of a characteristic rash, lymphadenopathy, organomegaly, or joint effusions. Systemic lupus erythematosus is unlikely, in light of the absence of fluorescent antinuclear antibody or antiDNA antibodies, and normal findings on complement studies. Although fever and thrombocytosis might suggest Kawasaki disease, the diagnostic clinical features are, again, notably absent. Persistent neutrophilic leukocytosis has been reported in association with functional asplenia. 9 The absence of Howell-Jolly bodies on our patient's peripheral-blood smear and the presence of a normal-appearing spleen by abdominal ultrasonography are reassuring, although a radioisotope spleen scan or pitted-erythrocyte study would provide definitive evidence of adequate splenic function. DISCUSSION FINDINGS

OF I M M U N O L O G I C

DR. FRIEDMAN: Several immunologic tests showed abnormalities in this patient. She was nonreactive to a Candida t: 100 skin test, suggesting a deficit in T-cell function, but more than half of the children of this age will be nonreactive to this test. A more accurate measure of T-cell function can be performed by testing in vitro responses to T-cell mitogens. The patient's serum IgG, IgE, and IgA concentrations were mildly elevated. An elevated serum level of IgE prompts consideration of the hyperimmunoglobulinemia E syndrome, a disease associated with marked leukocytosis and prominent eosinophilia. The diagnosis is a clinical one, with classic findings including coarse facies, recurrent staphylococcal head and neck abscesses, and pneumonias leading to pneumatocele formation. The immunologic profiles of these patients are heterogeneous. They often show normal in vitro mitogenic lymphocytic proliferation but poor lymphoproliferative and antibody response to neoantigens. In addition to elevations of IgE levels, the serum IgD concentration is often high, and diph-

The Journal of Pediatrics May 1992

theria and tetanus titers are usually low. 1~ Although our patient did have low titers, she had received only two immunizations; one must be cautious in interpreting these results as abnormal. In light of the lack of typical clinical findings in our patient, a diagnosis of the hyperimmunoglobulinemia E syndrome is unlikely. The mild elevation in her serum immunoglobulin levels is equally consistent with a history of recurrent infections. In this patient, disorders of leukocyte chemotaxis, adhesion, or microbicidal function should be strongly considered. All can result in recurrent infections and many are associated with leukocytosis. The best-known disorder of leukocyte microbicidal function is chronic granulomatous disease, which can be inherited in an X-linked or autosomal recessive manner, ll The essential defect is a lack of superoxide generation required for bactericidal activity. Patients with clinical CGD are particularly susceptible to infections by organisms that do not produce superoxide, most commonly S. aureus and Aspergillus species. 12 The clinical findings in most patients with CGD include frequent pulmonary infections, osteomyelitis, and granulomas of the liver, gastrointestinal tract, and genitourinary tract. 13 Leukocytosis and hypergammaglobulinemia are frequently found. 14 In the X-linked form of the disease, the defect is a lack of the/3 chain of cytochrome b245, a component of the electron transport chain. Patients with the autosomal recessive form of CGD have defects in one of several cytosolic factors for NADPH oxidase. 15 Results of the nitroblue tetrazolium test, a useful diagnostic screen, were normal in our patient, making CGD an unlikely diagnosis. Other diseases that fall into this category include neutrophil-specific granule deficiency and myeloperoxidase deficiency. 15 Ch6diak-Higashi syndrome, characterized by recurrent pyogenic infections, partial oculoeutaneous albinism, and giant cytoplasmic granules, is associated with neutropenia and characteristic cytoplasmic inclusion bodies in phagocytic cells. Abnormalities of leukocyte ingestion and chemotaxis can also arise from defective cytoskeletal protein interactions, especially those involving actin and actin-binding proteins. Abnormal leukocyte chemotaxis has been described in the lazy leukocyte syndrome, mannosidosis, protein-calorie malnutrition, diabetes mellitus, and Shwachman syndrome, which is characterized by pancreatic insufficiency, chondroplasia, and recurrent infection. However, in none of these disorders is granulocytosis a prominent finding. DISCUSSION MOLECULES

OF L E U K O C Y T E

ADHESION

DR. BRUGGERS: Leukocyte adhesion deficiency is a recently described, rare disorder of widespread leukocyte adhesion abnormality, characterized clinically by a leuko-

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cyte count on the order of 15,000 to 160,000 cells/mm 3, impaired pus formation, recurrent infections, impaired wound healing, and delayed separation of the umbilical cord. 16-24 Infections commonly involve the skin, mouth, gastrointestinal tract, and respiratory tract, and are most frequently due to S . aureus and gram-negative enteric organisms. The disease is inherited in an autosomal recessive manner,17 and fewer than 100 patients have been identified since the first group of patients was described in 1980. 21 The leukocytes of such patients show abnormalities of chemotaxis and phagocytosis, now known to be the result of a deficiency of specific cell-surface glycoproteins, called leukocyte adhesion molecules. The clinical severity of the disorder is directly related to the degree of glycoprotein deficiency. The impact of LAD on the immune system is marked, with decreased natural killer cell function, diminished antibody-dependent cellular cytotoxicity, and impaired iymphoproliferation to mitogens and antigens. A multiplicitY of abnormalities have been shown, including impairment of granulocyte-directed migration, cell-mediated cytotoxicity, phagocytosis of C3b opsonized particles, and tissue leukoCyte mobilization, a6, 17, 19 Despite normal to elevated Serum immunoglobulin levels, impairment in specific antibody production has been documented in several cases, with lack of response to diphtheria-tetanus-pertussi s immunization. The leukocyte adhesion molecules include three distinct but related cell-surface glycoproteins: leukocyte functionassociated antigen type 1, Mac-l, and p150,95. These glycoproteins are heterodimers and share a common 95kilodalton/3 chain, CD18, but have different ~ chains. The current nomenclature for the large and small subunits of LFA-1 are C D l l a and CD18, of Mac-1 are C D l l b and CD18, and of p150,95 are CD1 lc and CD18. ARhough differing in specific function, these molecules are intimately involved in cell adhesion and signaling. The glycoprotein LFA-1 is crucial in T-cell interaction with monocytes, B cells, and endothelial cells; in NK cells and T-cell cytotoxicity; in leukocyte chemotaxis; and in adhesion processes involving neutrophils, lymphocytes, and nonhematopoietic Cells. The glycoprotein Mac-1 functions as a receptor for C3bi, or complement-opsonized particles, as well as in leukocyte adhesion processes involving endothelial margination and tissue extravasation. Although less well characterized, p150,95 also serves as an important receptor for complement-opsonized particles. In all cases of LAD described t 9 dat e, there i s faulty production of the 13chain of the heterodimers. Several studies have shown that expression of the fi chain is linked to the proper transport and expression of the c~-fiheterodimer on the cell surface. Thus the result of/%chain deficiency is the absence of functional molecules of all three types. Het-

Infant with fever and neutrophilic leukocytosis

823

erozygous individuals generally do not manifest clinical symptoms; homozygous individuals can be divided into two clinical groups. Patients with less than 3% of normal expression are severely affected and have recurrent lifethreatening infections. Delayed umbilical cord separation is characteristic of this group and is often accompanied by omphalitis. Patients with 3% to 31% of normal glycoprotein expression are moderately affected. These patients are less prone to severe life-threatening infections, but they do experience repeated infections, and many have died in their third or fourth decade. 17, 19 Patients with moderate or severe disease have chronic gingivitis and periodontitis, resuiting in loss of deciduous and permanent teeth. It can be difficult to predict the eventual severity of the disease in patients with 3% to 10% of normal expression. Functional polymorphonuclear neutrophil studies may help the physician to categorize an individual patient. With the degree of leukocytosis in our patient, the history of delayed cord separation and omphalitis, and the nonpurulent gram-negative infection at the site of bone marrow biopsy, a diagnosis of LAD was strongly considered. DIAGNOSTIC

PROCEDURE

Immunofluorescent flow cytometry was performed, as were tests of lymphocyte proliferation to mitogens and function of NK cells. The patient had a high CD4+/CD8 + ratio of 6.8 (control 2.1), with normal lymphocyte responses to the mitogens phytohemagglutinin, concanavalin A, and pokeweed mitogen but low responses to tetanus and candidal antigens. Function of NK cells was completely lacking. Fluorescent staining of cytoskeletal proteins was not performed. The glycoprotein LFA-1 was absent on blood mononuclear cells, and approximately 1% to 2% of the normal LFA-1 value was found on the granulocytes. Granulocyte function studies of neutrophil migration, phagocytosis, and adhesion were performed by Dr. Donald Anderson, of Bayl0r College o f Medicine, Waco, Tex. The migration studies, including Boyden chamber chemotaxis, showed profound abnormalities. Results of all studies were consistent with the diagnosis of severe LAD. DIscussION

OF D E F I N I T I V E

THERAPY

DRS. KuRTZBERG AND GRAHAM: Despite the well appearance of this infant and her rapid clinical improvement with appropriate antibiotics, her prognosis, based on historical perspective with severe LAD, was extremely grim. Successful bone marro w transplantation has been reported in the treatment of severe cases of LAD 2527 and currently remains the treatment of choice. The patient was mainrained with prophylactic sulfamethoxazole-trimethoprim therapy and followed clinically for 7 months. During this time the patient's mother gave birth to a female infant who

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Fishbein et al.

had normal granulocyte function and normal L F A - 1 levels on blood mononuclear cells, and who was histocompatible (identical human leukocyte antigen complex and nonreactive mixed leukocyte culture) with the patient. When the patient was 14 months of age, allogeneic bone marrow transplantation was performed after conditioning with busulfan at 1 m g / k g every 6 hours for 16 doses and cyclophosphamide at 50 m g / k g per day for 4 days. Prophylaxis for graft-versus-host disease included cyclosporine and methotrexate. No significant complications occurred, and engraftment was apparent in 10 days. On full hematopoietic recovery the patient's granulocyte functions and L F A - 1 levels were reevaluated. Function of N K cells and granulocyte chemotaxis were normal. Reactivity of peripheral blood mononuclear cells to LFA-1 revealed two cell populations, one L F A - l - n e g a t i v e (18%) and one with normal expression (82%), indicating bone marrow chimerism. The patient remains well and without infections 6 months after bone marrow transplantation. REFERENCES

1. Nathan DG, Oski FA. Hematology of infancy and childhood. Philadelphia: WB Saunders, 1987:814. 2. Touhy EL. A case of splenomegaly with polymorphonuclear neutrophil hyperleukocytosis. Am J Med Sci 1920; 160:18-25. 3. Lorente JA, Pefia JM, Ferro T, et al. A case of chronic neutrophilic leukemia with original chromosomal abnormalities. Eur J Haematol 1988;41:285-8. 4. Eichenhorn MS, Van Slyck EJ. Marked mature neutrophilic leukocytosis: a leukemoid variant associated with malignancy. Am J Med Sci 1982;284:32-5: 5. Herring WB, Smith LG, Walker RI, Herion JC. Hereditary neutrophilia. Am J Med 1974;56:729-34. 6. Watanabe H, Yamanaka T. Ring chromosome 22 46,XX, r(22) (pl 1.2-q 13.3) presenting with leukemoid reaction. Clin Genet 1988;34:206-7. 7. Seibel NL, Sommer A, Miser J. Transient neonatal leukemoid reactions in mosaic trisomy 21. J PEOXATR1984;104:251-4. 8. Ganick DJ. Hematological changes in Down's syndrome. Crit Rev Oncol Hematol 1986;6:55-69. 9. Spencer RP, McPhedran P, Finch SC, Morgan WS. Persistent neutrophilic leukocytosis associated with idiopathic functional asplenia. J Nucl Med 1972;13:224-6. 10. Buckley RH, Sampson HA. The hyperimmunoglobulinemia E syndrome. In: Franklin EC. Clinical immunology update. New York: Elsevier, 1981 :147-67. 11. Curnutte JT, Babior BM. Chronic granulomatous disease. Adv Hum Genet 1987;16:229-97. 12. Gallin JI, Malech HL. Update on chronic granulomatous diseases of childhood. JAMA 1990;263:1533-7.

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13. Mouy R, Fischer A, Vilmer E, Seger R, Griscelli C. Incidence, severity and prevention of infections in chronic granulomatous disease. J PEDIATR 1989;114:555-60. 14. Quie PG, Abramson JS. Disorders of the polymorphonuclear phagocyte system. In: Stiehm ER, ed. Immunological diseases in infants and children. 3rd ed. Philadelphia: WB Saunders, 1989:343-63. 15. Curnutte JT, Berkow RL, Roberts RL, Shurin SB, Scott PJ. Chronic granulomatous disease due to a defect in the cytosolic factor required for nicotinamide adenine dinucleotide phosphate oxidase activation. J Clin Invest 1988;81:606-10. 16. Todd RF III, Freyer DR. The CD11/CD18 leukocyte glycoprotein deficiency. Hematol Oncol Clin North Am 1988;2:1331.

17. Fischer A, Lisowska-Grospi~rre B. Leukocyte adhesion deficiency: molecular basis and functional consequences. Immunodefic Rev 1988;1:39-54. 18. Anderson DC, Springer TA. Leukocyte adhesion deficiency: an inherited defect in the Mac-l, LFA-1, and p150,95 glycoproteins. Ann Rev Med 1987;38:175-94. 19. Anderson DC, Schmalsteig FC, Finegold M J, et al. The severe and moderate phenotypes of heritable Mac-l, LFA-1 deficiency: their quantitative definition and relation to leukocyte dysfunction and clinical features. J Infect Dis 1985;152:66889. 20. Abramson JS, Mills EL, Sawyer MK, Regelmann WR, Nelson JD, Quie PG. Recurrent infections and delayed separation of the umbilical cord in an infant with abnormal phagocytic cell locomotion and oxidative response during particle phagocytosis. J PEDIATR 1981;99:887-94. 21. Crowley CA, Curnutte JT, Rosin RE, et al. An inherited abnormality of neutrophil adhesion: its genetic transmission and its association with a missing protein. N Engl J Med 1980; 302:1163-8. 22. Ross GD. Clinical and laboratory features of patients with an inherited deficiency of neutrophil membrane complement receptor type 3 (CR3) and the related membrane antigens LFA-1 and p150,95. J Clin Immunol 1986;6:107-13. 23. Marlin SD, Morton CC, Anderson DC, Springer TA. LFA-1 immunodeficiency disease. J Exp Med 1986;164:855-67. 24. Wardlaw A J, Hibbs ML, Stacker SA, Springer TA. Distinct mutations in two patients with leukocyte adhesion deficiency and their functional correlates. J Exp Med 1990;172:335-45. 25. Fischer A, Descamps-Latscha B, Gerota I, et al. Bone-marrow transplantation for inborn error of phagocytic cells associated with defective adherence, chemotaxis, and oxidative response during opsonised particle phagocytosis. Lancet 1983;2:473-6. 26. LeDeist F, Blanche S, Keable H, et al. Successful HLA-nonidentical bone marrow transplantation in three patients with the leukocyte adhesion deficiency. Blood 1989;74:512-6. 27. Fisher A, Blanche S, Veber F, et al. Correction of disorders by HLA matched and mismatched bone marrow transplantation. In: Gale PR, Champlin R, eds. Progress in bone marrow transplantation. New York: Alan R. Liss, 1987:911-8.