From Department of Paediatric Immunology and Leukocyte Biology, National Institute of Immunohaematology (ICMR), 13th Floor, NMS Bldg, KEM Hospital, Parel, Mumbai; and , *Department of Immunology,
Bai Jerbai Wadia Hospital for Children, Acharya Donde Marg, Parel, Mumbai; India.

 PII: S09747559INPE1000387-2
 

The exact incidence of LAD-I is not known, but it is estimated to be one in one million. In India, as there is a very high rate of consanguineous marriages in certain communities, a relatively higher frequency of this recessive disorder is expected; however, except few case reports [8,9], no comprehensive study has been published from this subcontinent. Here we report clinical profile of 7 cases of LAD-I diagnosed over a period of 3 years.

The study group included 7 patients from 6 unrelated families. These families were from different parts of India: 5 from western India and 1 from south India. 4 index cases along with their parents were investigated whereas in 2 cases parents were not available for study. The clinical details including birth weight, presenting complaints, time of separation of umbilical cord, number of infections, site of infections, treatment required, organisms causing the infection, were recorded at the time of diagnosis.

Complete hemogram with peripheral smear examination was performed on all the cases. The diagnosis was done by studying the expression of CD18, CD11a, CD11b and CD11c on neutrophils and lymphocytes using multi-parametric flowcytometry. Nitro Blue Tetrazolium test (NBT), lymphocyte subset analysis and immunoglobulin estimation was done in all the patients to rule out other immunodeficiency disorders.

All the patients presented below the age of 2 years. There was positive family history in the form of early death in the sibling due to infection was present in 3 cases. History of consanguineous marriage in the parents was present in 3 cases. History of early death in the sibling due to infections was present in 4 families. Recurrent skin and mucous membrane infections were the major presenting complaints in these patients (Table I). In one patient omphalitis required surgical intervention.

TABLE I Clinical Details of Patients

Follow up was available in all 7 of these children and 6 of them expired due to septicemia within 1 year after diagnosis. One patient is alive and is 4 month of age. He was diagnosed at birth as the previous child in the family had LAD-I. He is on antibacterial and antifungal prophylaxis, but requires frequent  hospitalization due to infections.

The data from seven patients suggests that LAD-I should be suspected in any infant with serious infections accompanied by striking neutrophilia in the peripheral blood. Absence of neutrophilia in a newborn infant who has delayed cord separation but is otherwise well generally rules out the diagnosis. Infections vary from severe bacterial infections to fungal disease. The white blood cell count ranges between 15 - 160 × 10⁹/litre and 50–90% of these are neutrophils [7]. The diagnosis can be easily established by studying the expression of CD11 and CD18 on leukocytes by flowcytometry. However, this facility is not available widely in India and hence majority of these cases remain undiagnosed. Leukocyte activation before flow cytometry can greatly enhance the expression of these glycoproteins and magnify the differences between healthy subjects and patients [10]. Other LAD disorders like LAD-II, and LAD-III should be kept in mind while evaluating patients with suspected leukocyte adhesion defects. LAD type II syndrome results from a general defect in fucose metabolism, causing the absence of SLeX and other fucosylated ligands for the selectins [11]. Affected patients present early in life, have recurrent bacterial infections with persistent leukocytosis, but do not have delayed separation of the umbilical cord. The infections are generally not life threatening. These patients also have severe mental retardation, short stature, a distinctive facial appearance and the rare Bombay (hh) blood phenotype. The diagnosis can be done by studying SLeX expression on leukocytes. Recently, a rare autosomal recessive LAD-III syndrome has been described presenting with recurrent severe bacterial infections, leukocytosis and severe bleeding tendencies. CD18 molecule is structurally intact in these patients and they show significant abnormalities in leukocyte and platelet integrin activation. Defects both in Kindlin 3 and CAL-DAG-GEF1 were found to cause LAD III [1,12].

There are very few therapeutic options available for patients with LAD-I. Supportive care is usually not sufficient in the severe form of disease and majority of the children die before the age of 5 years. The only curative option available for these patients is hematopoietic stem cell transplantation. Facilities for hematopoietic stem cell transplantation are not widely available and the cost is prohibitive for majority of the patients in India. Thus, preventing birth of a second child with LAD-I in affected family becomes extremely important. Leucocytes express CD18 and CD11 at 20 weeks gestation and at this time blood can be obtained by cordocentesis for prenatal diagnosis [19]. We have established normal ranges for expression of CD18 and CD11 at 18 weeks of gestation and have started the facility for prenatal diagnosis of LAD-I. Mutational analysis on chorionic villous biopsy or cells obtained by amniocentesis may also be possible when the precise familial mutation is known. However, this facility is not available in India.

Contributors: MM and ZC conceived and designed the study and revised the manuscript for important intellectual content. They will act as guarantor of the study. GM, ZC, MD and RM collected data and drafted the paper. GM and RM also conducted the laboratory tests, and interpreted them. ZC, MD and MM analyzed the data and helped in manuscript writing. The final manuscript was approved by all authors.

Funding: None; Competing interests: None stated.

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