Indian Pediatrics 2002; 39:963-966
Leucocyte Adhesion Deficiency-1
Leucocyte adhesion deficiency (LAD) disorders, LAD-1 and LAD-2 are rare diseases of leucocyte function with an autosomal recessive mode of inheritance. LAD-1 results from a lack of leucocyte cell surface expression of B2 integrin molecules (CD 11 and CD 18) that are essential for leucocyte adhesion to endothelial cells and chemotaxis(1). This disorder is characterized by delayed separation of the umbilical cord, recurrent life-threatening infections of the oral and genital mucosa, skin, intestine and respiratory tract. There is also impaired pus formation and delayed wound healing despite extreme neutrophilia, which occurs especially during infections(2). Children with LAD-1 who have no detectable CD18 have the worst prognosis and most die by the age of 10 years(3).
LAD-2 presents with the same clinical features as LAD-1 but the CD11/CD18 integrins are normal. The neutrophils in this condition are deficient in the surface membrane carbohydrate structure, sialyl-Lewis X which is essential for adherence to activated endothelial cells(4). We report a case of LAD-I in an infant who presented with characteristic clinical findings, and the diagnosis was confirmed by flow cytometry. Though LAD-1 has been reported elsewhere in the world, we were unable to find any previous case reported from India.
A 3½-month-old female infant was brought with a history of low-grade intermittent fever for 2 months, progressive abdominal distension, pallor, refusal of feeds and excessive crying for 1 month. She also had a spontaneous large non-healing ulcer on the left forearm for the last 1 month with no purulent discharge. She was admitted elsewhere prior to 2 weeks and treated with intravenous cefotaxime, amikacin and metronidazole for 2 weeks as Enterobacter sp. was isolated from blood culture and Pseudomonas aeruginosa from the ulcer base. She was referred here for further evaluation. She is the first child of third degree consanguineous parents born at term by cesarean section following an uncomplicated pregnancy. The umbilical cord separated on the 33rd postnatal day. There was no history suggestive of sepsis or umbilical infection in the neonatal period. She attained social smile by 2 months and had not yet developed head control. There was no family history of similar illness.
On examination, the infant was febrile and drowsy. Her weight was 3700 grams (birth weight was 3000 grams). She appeared pale; had no icterus, significant lymph node enlargement or mucocutaneous bleeds. Her vital signs were stable. She had no dysmorphic features. A 3×3 cm oval, dry, indurate, crusting ulcer with an undermined edge was present on the left forearm. A similar ulcer was also seen in the oral cavity at the base of the tongue. BCG scar was present. The liver was palpable 7 cm below the costal margin in the right midclavicular line and the spleen was palpable 2 cm along its long axis. Examination of other systems did not reveal any abnormality.
Investigations revealed hemoglobin concentration of 6.5 g/dL, platelet count of 615,000/cu mm, total leukocyte count of 120,000/cu mm with a differential count of myelocytes 3%, band forms 10%, neutrophils 78%, eosinophils 2%, lymphocytes 6% and monocytes 1%. Blood culture did not yield any organism, probably because the child had already received antibiotics. Serum immunoglobulin profile revealed IgG 1462 mg/dL (normal for age: 196-558 mg/dL), IgM 303 mg/dL (27-101mg/dL) and IgA 256 mg/dL (4.4-73 mg/dL). Serum complement and lactate dehydrogenase were normal. Bone marrow examination revealed myeloid hyperplasia, mild erythroid hyperplasia and no evidence of malignancy. Liver function tests were also within normal limits. Flow cytometry was done using a mouse monoclonal antibody to CD 11b; the neutrophil population was gated and in the normal controls 98.5% of the cells expressed the antigen while the patient cells were negative. Antibodies to CD 18 were not available. With the characteristic clinical features and confirmatory flow cytometry, a diagnosis of LAD-1 was made. The infant was treated with intravenous ceftazidime for 7 days; she became afebrile 48 hr after starting ceftazidime and ulcers healed by 7 days. The parents were counseled in detail about the nature of the illness. Options for treatment including bone marrow transplantation and course of action in future pregnancies were also explained They were also advised to treat all subsequent infections promptly with appropriate antibiotics.
The cellular elements of the immune system i.e., the neutrophils, monocytes/macrophages, T and B lymphocytes and other leukocytes communicate with each other, the endothelial surfaces and extracellular matrix leading to modulation of the immune and inflammatory responses and this communication is essential for cell trafficking(5). Some of these interactions are dependent on cytokines, while others require firm leucocyte-cell or leucocyte-matrix contact called adhesion(6). The b2 integrin (CD11/CD18), a glycoprotein complex, is required for adhesion dependent functions such as aggregation, spreading on substrates, chemotaxis, phagocytosis, cell-mediated killing and adherence to endothelium(5).
Leucocyte adhesion deficiency is characterized by the inability of leucocytes, especially neutrophils, to emigrate from the blood stream towards sites of inflammation. Infectious foci are therefore non-purulent and eventually become necrotic because of abnormal wound healing. The genetic defect in LAD-1 has been mapped to mutations of the gene encoding for CD18 on chromosome 2Iq22.3.
Our patient presented with severe infection, non-purulent, non-healing ulcers and a very high neutrophil count. There was also a history of delayed umbilical cord separation. The mean time of cord separation is about 7.4 days; cord separation can be delayed with antibiotic administration in sepsis, prematurity and delivery by cesarean section(7). The association of delayed umbilical cord separation and leucocyte dysfunction has been recorded in many cases(8,9); but delayed separation of the umbilical cord is not always necessarily accompanied by leucocyte dysfunction(7).
The differential diagnosis considered were infection with leukemoid reaction, congenital leukemia or an immunodeficiency disorder. Serum immunoglobulins, complement levels and BCG scar formation were normal. Bone marrow examination ruled out hematological malignancy. With the characteristic clinical features of delayed umbilical cord separation, severe infection despite extreme neutrophilia, non-purulent ulcers it was decided to investigate this child for leucocyte adhesion defects. The absence of CD 11b on the patient’s neutrophils detected by flow cytometry confirmed the diagnosis of LAD-l in our case. Patients with undetectable CD 11/CD18 surface glycoproteins are prone to severe life-threatening systemic infections like sepsis, pneumonia, meningitis and peritonitis. Patients with diminished (3% to 10% of normal) CD11/CD18 surface glycoprotein have less severe infections and chronic periodontitis.
LAD usually results in recurrent necrotic and indolent infections of soft tissue, skin and mucous membranes without pus formation. Recurrent otitis, sinusitis, pneumonia, perirectal abscess and cellulitis are common. Gingivitis and periodontitis are a constant feature in later childhood. The most common pathogens causing infection in LAD are Staph. aureus, Pseudomonas sp., other gram negative enteric species and Candida albicans(10). The clinician must be aware of the possibility of LAD in a child with recurrent and severe infections, often with persistently high leucocyte counts. The diagnosis of LAD-1 is confirmed by examining the neutrophils for surface expression of CD11/CD18 molecules by immunofluorescence and flow cytometry.
We sincerely thank Mr. Stany Amirtharaj GRT, Department of Hematology, Christian Medical College and Hospital, Vellore for performing the flow cytometry analysis.
Contributors: AS compiled the data and prepared the manuscript. SP assisted in drafting the manuscript and was involved in the management of the patient. MC interpreted the flow cytometry results and helped in editing the manuscript. PR was the overall co-ordinator and guide; he will act as guarantor for this paper.
Competing interest: None stated.