Year : 2022 | Volume
: 13 | Issue : 1 | Page : 54--56
Leukocyte adhesion defects Type III: A rare association of primary immunodeficiency and platelet functional defect
Division of Paediatric Haematology-Oncology, St John's Medical College Hospital, Bengaluru, Karnataka, India
Dr. Anand Prakash
Division of Pediatric Hematology-Oncology, Department of Pediatrics, St John's Medical College Hospital, Bengaluru - 560 034, Karnataka
Leukocyte adhesion defect (LAD) Type III is an extremely rare disease, which presents with severe infections and a Glanzmann thrombasthenia-like bleeding phenotype. A 2-year-old male child with LAD Type III with recurrent mucosal bleeding and relatively few infections is presented to highlight this novel presentation. The rare association of primary immunodeficiency and platelet functional disease is described.
|How to cite this article:|
Prakash A. Leukocyte adhesion defects Type III: A rare association of primary immunodeficiency and platelet functional defect.J Appl Hematol 2022;13:54-56
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Prakash A. Leukocyte adhesion defects Type III: A rare association of primary immunodeficiency and platelet functional defect. J Appl Hematol [serial online] 2022 [cited 2022 Jun 26 ];13:54-56
Available from: https://www.jahjournal.org/text.asp?2022/13/1/54/344265
Leukocyte adhesion defects (LADs) are a group of rare disorders of primary immunodeficiency. It is characterized by early onset of superficial infections associated with neutrophilic leukocytosis, delayed umbilical cord fall, and absence of pus in the areas of infection. A very rare variant of leukocyte adhesion disorder, LAD Type III is associated with a severe bleeding tendency and has been described in a few reports from Turkey, the Middle East, and the USA.,,, We present a case of LAD Type III with a severe bleeding tendency but less severe infections, which to our knowledge is the first such report from India. This case is reported to describe the rare association of primary immunodeficiency and platelet functional defect. It also highlights the uncommon phenotype of less severe infections but more severe bleeding in this variant of LAD where classically infections occur early and have a severe phenotype. Written informed consent was obtained from the parents for this case report.
A 2-year-old boy was referred for recurrent bleeding from the skin and gums since 1 year of age. He was the second child born to a nonconsanguineous parentage with a history of previous sibling death on day 1 of life following pulmonary bleeding. Other family members were well with no bleeding tendency. The index case was born at term gestation, had birth asphyxia, and required treatment for suspected neonatal sepsis for 27 days. The child had also been treated for an episode of pneumonia at 6 months of age. He had no other superficial or deep seated infections. At 1 year of age, the child had been having episodes of gum bleeding. Clinical examination revealed both wasting and stunting (weight and height below 3rd centile) with pallor, but other examination was unremarkable. His serial laboratory tests revealed a persistently elevated total leukocyte count with neutrophilic leukocytosis and a normal platelet count. Coagulation work-up showed normal prothrombin time, activated partial thromboplastin time, and fibrinogen. His platelet aggregometric studies showed decreased aggregation to adenosine diphosphate (ADP), epinephrine, and collagen with a normal response to ristocetin, a pattern seen in Glanzmann thrombasthenia (GT). In view of the persistent leukocytosis, a possibility of LAD Type III was considered and clinical exome evaluation by next-generation sequencing was performed. A homozygous single base pair insertion in exon 4 of the FERMT3 gene (chr11) was detected. On follow-up over 3 years, he continues to have frequent severe gingival bleeds requiring multiple admissions for supportive platelet and red cell transfusions. He has not had any severe infections. Considering the severe bleeding phenotype, the option of hematopoietic stem cell transplantation has been offered to the family.
LAD Type III is an extremely rare form of immunodeficiency characterized by features of severe infections akin to LAD Type I and also a bleeding disorder with a GT-like phenotype. It was first described in 1997. Most patients reported have a consanguineous parentage. Like LAD type I, many neonates have a delayed cord fall of more than 4 weeks. Infections described in these patients include Gram-negative (Escherichia coli, Pseudomonas species) and also staphylococcal species. Both superficial and deep infections by fungi such as Aspergillus and Fusarium have been described.
There are only a few reports of LAD III, all with varied clinical presentation. The report by Kuijpers et al. described a male infant from Turkey who had delayed cord fall at 5 weeks, delayed wound healing, and recurrent inflammatory lesions. The bleeding tendency manifested only by 2 years of age. Neonatal sepsis, as seen in our case, has been described by Alon et al. in two siblings of Arab descent both of whom had neonatal sepsis, being fatal in one of them. Kuijpers et al. report nine patients with a variant of LAD Type I which is now designated as Type III LAD. Patients in this series all presented with both infection and bleeding in early infancy. Recurrent bleeding required multiple episodes of supportive platelet and packed cell transfusions as seen in our case.
Leukocyte adhesion deficiency Type III (OMIM#612840) is caused by homozygous or compound heterozygous mutations in the FERMT3 gene (OMIM *607901). This FERMT3 variant described here has not been reported in both the 1000 genomes and ExAC databases and is probably a novel mutation. We unfortunately could not perform genetic analysis on the parents to confirm this variant due to cost of testing. LAD Type III is caused by homozygous mutations in the FERMT3 gene (11q13.1), which encodes kindlin-3. These mutations are known to activation defects of all beta-integrins. In LAD Type III, the adhesive functions of integrins on both leukocytes and platelets are disrupted. Neutrophilic leukocytosis is often seen as in other patients with LAD. The severity of manifestations varies from mild to severe. The various mutations in the FERMT3 gene may be responsible for the varied severity in manifestations. Platelet aggregation assays mimic GT, with the aggregation response to ADP, epinephrine, and collagen being decreased and response to ristocetin being normal. This is because of the lack or dysfunction of the fibrinogen receptor GPIIb/IIIa (integrin αIIbβ3). The severity of bleeding is described to be more severe in LAD Type III. Classic aggregometry does not help in distinguishing these disorders. A novel flow cytometry-based aggregation assay has been described to help differentiate LAD Type III from GT. Management is largely supportive and the only curative option is stem cell transplantation. During severe infections, the use of granulocyte transfusion has been reported to be useful. Stem cell transplant has been successful in LAD Type III; however, there have been challenges in terms of transplant-related mortality and rejection.
This case highlights the rare association of platelet functional defect with primary immunodeficiency, with a phenotype of severe bleeding but less frequent infections, not previously described in India. This novel mutation seen in our patient may be the reason for the phenotype with more severe bleeding than infections. It is vital for clinicians to keep this rare association in mind, especially in children who present with a phenotype of GT.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient's parents have given consent for images and other clinical information to be reported in the journal. The patient's parents understand that the names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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