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Indian Pediatr 2012;49: 43-45
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Clinical Profile of Leukocyte Adhesion
Deficiency Type I |
M Madkaikar, *Z Currimbhoy, M Gupta, *M Desai and M Rao
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.
Correspondence to: Dr Manisha Madkaikar, National
Institute of Immunohaematology, 13th Floor, NMS Bldg,
KEM Hospital, Parel, Mumbai 400012, India.
Email:
[email protected]
Received:October 29, 2010;
Initial review: January 12, 2011;
Accepted: March 25, 2011.
Published online: 2011, May 30.
PII: S09747559INPE1000387-2
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Abstract
Leukocyte adhesion deficiency type I (LAD-I) is a
rare, inherited immunodeficiency with defect in the recruitment of
leukocyte to the site of inflammation. Patients with severe LAD-I have
absent or markedly reduced expression of CD18 and CD11. Here we report
clinical profile of 7 cases of LAD-I diagnosed at our center over a
period of 3 years. Recurrent skin and mucous membrane infections were
the major presenting manifestations. All children had a history of
delayed cord separation.
Key words: Inherited immunodeficiency, Leukocyte adhesion
deficiency (LAD-I), Neutrophilia.
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Leukocyte adhesion deficiency (LAD) syndromes result
from failure of leukocytes to defend the host because of missing or
dysfunctional surface adhesion molecules [1]. LAD-I (OMIM 116920) results
from mutations in the ITGB2 gene encoding for the β2 subunit
(CD18) of beta 2-integrin [2-5]. It is the commonest of the LAD syndromes
with more than 300 cases reported worldwide. Patients usually present soon
after birth with omphalitis and delayed separation of the cord (often
beyond 21 days) [6,7]. The prominent clinical feature of these patients is
recurrent bacterial infections, primarily localized to skin and mucosal
surfaces [6,7]. Life threatening infections such as septicemia,
bronchopneumonia, and aseptic meningitis can occur. The most frequent
organisms involved are S. aureus, Gram negative enteric organisms,
and fungi. The severity of infections and complications is related to the
severity of CD18 deficiency; cases with < 1% expression are clinically
severe, whereas those with 2.5–10% expression are moderate to mild [1].
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.
Methods
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.
Results
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
Clinical presentation |
Patient 1 |
Patient 2 |
Patient 3 |
Patient 4 |
Patient 5 |
Patient 6 |
Patient 7 |
Age/Sex |
3 m/ M |
6 days/M |
4 m/F |
9 m /M |
4 m /F |
2.5m/F |
2y/F |
First symptoms |
Omphalitis |
Omphalitis |
Omphalitis, |
Perianal |
Omphalitis |
Omphalitis |
Omphalitis |
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otitis media |
abscess |
otitis |
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Average no. of infections/ y |
7 |
6 |
8 |
5 |
4 |
7 |
3 |
Bacterial infections
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S. aureus |
NA |
S.aureus,
Pseudomonas |
Streptococcus |
Pseudomonas |
E. Coli |
S. aureus |
Viral infections |
No |
No |
No |
No |
No |
NA |
NA |
Fungal infections |
No
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No
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No
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No
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NA
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Oral Candidiasis |
NA
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Necrotic skin lesions |
Yes |
Yes |
Yes |
Yes |
Yes |
Yes |
Yes |
Late detachment of cord |
Yes |
Yes |
Yes |
Yes |
Yes |
Yes |
Yes |
Transfusion |
Yes |
No |
Yes |
No |
No |
Yes |
No |
Birthweight (g) |
3000 |
NA |
2500 |
1700 |
2700 |
3700 |
NA |
Consanguineous marriage |
No |
No |
Yes |
No |
No |
Yes |
No |
Growth* |
NA |
NA |
25 |
25 |
50 |
NA |
NA |
All patients had poor wound healing and dysmorphic features; NA: No information available,
*Percentiles according to local growth charts.
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TABLE II Hematological Parameters and Expression of CD18/CD11 in the Seven Patients
Parameters |
Family 1 |
Family 2 |
Family 3 |
Family 4 |
Family 5 |
Family 6 |
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Patient 1 |
Patient 2 |
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Hb level (g/dL) |
11.5 |
12.2 |
6.8 |
9.8 |
8.5 |
7.3 |
9.2 |
Platelet count (×103/mL) |
300 |
312 |
424 |
416 |
355 |
562 |
532 |
% Neutrophils |
63 |
56 |
45 |
61 |
50 |
60 |
73 |
WBC count (×103/mL) |
58 |
34 |
64.2 |
24 |
29.7 |
23.5 |
50 |
% Lymphocytes |
25 |
40 |
15 |
31 |
40 |
35 |
23 |
CD11/CD18 expression (%) |
0.5 |
0.5 |
0.3 |
1.8 |
0.5 |
0.3 |
0.3 |
Table II shows the hematological parameters and
expression of CD18/CD11 in the patients. All patients had neutrophilia and
ANC at the time of diagnosis ranged from 14100 to 63500/mm3.
The CD18/CD11 expression ranged from 0% - 2% in all the patients
suggesting severe LAD-I. All the patients were deficient for CD11a, CD11b
and CD11c along with CD18. The expression in parents ranged from 95-100%.
The infectious agents cultured were S. aureus, streptococci and
Pseudomonas. Fungal disease was documented only in one child who had
persistent oral candidiasis. Repeated skin infections especially in
perianal area were common. One patient has repeated episodes of bacterial
meningitis, whereas two patients had repeated otitis media caused by
pseudomonas infection. Splenomegaly and hepato-megaly was observed in one
patient. None of the patients had any hematologic malignancy or solid
tumors.
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.
Discussion
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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