Leukocyte adhesion defect type 1 presenting with recurrent pyoderma gangrenosum.

Leukocyte adhesion deficiency 1 (LAD-1) is a rare autosomal recessive disorder of leukocyte function. LAD-1 affects about 1 per 10 million individuals and is characterized by recurrent bacterial and fungal infections and depressed inflammatory responses despite striking blood neutrophilia. Patients with the severe clinical form of LAD-1 express <0.3% of the normal amount of the β2-integrin molecules, whereas patients with the moderate phenotype may express 2-7%. Skin infection may progress to large chronic ulcers with polymicrobial infection, including anaerobic organisms. The ulcers heal slowly, require months of antibiotic treatment, and often require plastic surgical grafting. The diagnosis of LAD-1 is established most readily by flow cytometric measurements of surface CD11b in stimulated and unstimulated neutrophils using monoclonal antibodies directed against CD11b. Pyoderma gangrenosum (PG) is an uncommon condition characterized by recurrent sterile, inflammatory skin ulcers. Commonly, PG occurs in the context of inflammatory bowel disease or rheumatic, hematologic, or immunologic disorders. Here, we present a 5-year-old female with a long history of PG, which healed with atrophic scarring, who was ultimately diagnosed with leukocyte adhesion deficiency type 1 (LAD1). She had a good response to high-dose prednisone therapy (2 mg/kg) and was discharged after 3 weeks of admission but only to be re-admitted 3 weeks later with severe pneumonia. During hospital stay, she developed pneumothorax and pneumomediastinum and later succumbed to her illness.

What was known?

Pyoderma gangrenosum (PG) is an uncommon condition characterized by recurrent sterile, inflammatory skin ulcers. Commonly, PG occurs in the context of inflammatory bowel disease or rheumatic, hematologic, or immunologic disorders. Leukocyte adhesion deficiency type 1 is an autosomal recessive disorder caused by absence or defect of the b2 integrin subunit (CD18). Individuals with LAD suffer from bacterial infections beginning in the neonatal period. Infections such as omphalitis, pneumonia, gingivitis, abscesses, and peritonitis are common and often life-threatening due to the patient's inability to properly destroy the invading pathogens.

Introduction

Leukocyte adhesion deficiency 1 (LAD-1) is a rare autosomal recessive disorder of leukocyte function.LAD-1 affects about 1 per 10 million individuals[1] and is characterized by recurrent bacterial and fungal infections with reduced inflammatory response despite marked blood neutrophilia. Children with severe disease present in infancy with recurrent, indolent bacterial infections of the skin, mouth, respiratory tract, lower intestinal tract, and genital mucosa. They may have a history of delayed separation of the umbilical cord, usually associated with infection of the cord stump. Skin infection may progress to large chronic ulcers with polymicrobial infection, including anaerobic organisms. The ulcers heal slowly, require months of antibiotic treatment, and often require surgical grafting. The pathogens infecting patients with LAD-1 are similar to those affecting patients with severe neutropenia and include Staphylococcus aureus and enteric gram-negative organisms such as Escherichia coli. These patients are also susceptible to fungal infections such as Candida and Aspergillus. The typical signs of inflammation such as swelling, erythema, and warmth may be absent. Pus does not form, and few neutrophils are identified microscopically in biopsy specimens of infected tissues. Despite the paucity of neutrophils within the affected tissue, the circulating neutrophil count during infection typically exceeds 30,000/μL and can surpass 100,000/μL. During intervals between infections, the peripheral blood neutrophil count may chronically exceed 12,000/μL. LAD-1 genotypes producing moderate amounts of functional integrins at the surface of the neutrophil significantly reduce the severity and frequency of infections compared to children with the severe form. Pyoderma gangrenosum (PG) is a rare, non-infectious neutrophilic dermatosis. Clinically, it begins with sterile pustules that rapidly progress and turn into painful ulcers of variable depth and size with undermined violaceous borders. In many cases, PG is associated with inflammatory bowel disease, rheumatic disorder, or neoplasia.[2-4] The diagnosis of LAD1 should be considered in all patients with unexplained skin ulcers, even in the absence of serious infections. Clinicians should be careful in making a diagnosis of idiopathic PG and consider LAD1 in the defferential diagnosis. This case report highlights the importance of the diagnosis of LAD1 being considered in all patients with unexplained skin ulcers, even in the absence of serious infections.

Patient Presentation

Five-year-old female child, second product of non-consanguineous marriage, resident of New Delhi, presented with recurrent skin lesions, often occurring in areas of previous trauma (pathergy) since the age of 6 months. The lesions exhibited stereotypical phases: Initial small erythematous, tender papules developed into pustules, which coalesced and formed deep ulcerations with necrotic borders and overhanging edges, typical of PG. Wound healing was delayed, and the scars were unusual with the healed skin being thin, soft, and lax & atrophic. The episodic ulcerations were often accompanied by peripheral neutrophilic leukocytosis (granulocytosis) and elevated acute-phase reactants. Repeated evaluations for inflammatory bowel disease, hematologic, and rheumatic diseases were negative. There was no history of delayed umbilical cord separation, omphalitis, recurrent chest infections, diarrhea, oral thrush, or periodontitis. On examination, at admission, she had stable vitals. There was mild pallor. Multiple tender ulcerative lesions with typically undermined and violaceous or bluish ulcer borders with peri-lesional erythema and edema were present over lower limbs [Figure 1] and chest. Insignificant cervical lymphadenopathy was present. Her weight and height were appropriate for age and sex. Systemic examination was unremarkable. On investigation, hemoglobin (Hb) was 6.0 g/dl, hematocrit (Hct) was 18.3, total leukocyte count (TLC) 43,600 per μL with polymorphs 88%, lymphocytes 5%, monocytes 7%, platelet count 1,95,000 per μL, and erythrocyte sedimentation rate (ESR) was 73 mm/1st hour by Westergren method. Peripheral smear showed normocytic normochromic red cells with neutrophilic leukocytosis and toxic granules. Bone marrow aspiration showed neutrophilic leukocytosis with cellular marrow. Blood urea creatinine and serum electrolytes were normal. Serum total protein of 6.2 gm and albumin of 3.2 gm per 100 ml of blood. Serum C3 level was 130 mg/dl (N 90-180 mg/dl). Serum CRP was negative. Anti-nuclear antibody and rheumatoid factor were negative. HIV was non-reactive. Peri-lesional pus culture sensitivity was sterile. Blood and urine cultures showed no growth. Skin biopsy was suggestive of neutrophilic dermatosis [Figure 2]. Immunoglobulin assay Ig A was- 65.4 mg/dL (N 30-240 mg/dl), Ig G-661.0 mg/dL (N-610-1380 mg/dL), IgM 169.8 mg/dL (N-20-134 mg/dL). Subsequently, the diagnosis of LAD1 was made by demonstrating reduced neutrophil CD11b surface expression (by flow cytometry). Neutrophil chemotaxis studies showed a decrease in directed chemotaxis.

Figure 1

Illustration of the typical progression of skin lesions in our patient

Figure 2

Lightmicroscopic findingsof skin lesions

Child received i.v. antibiotics (ceftriaxone, amikacin, ceftazidime) along with prednisolone (2 mg/kg) for pyoderma gangrenosum. The lesions healed and child improved clinically, hence discharged after 3 weeks of admission [Figure 3].

Figure 3

Pictures of patient post-initiation of steroids

She was re-admitted after 2 weeks with severe pneumonia. Within 24 fours of admission, she developed pneumothorax and pneumomediastinum [Figure 4] and later succumbed to her illness.

Figure 4

Chest x-ray showing pulmonary infiltrates, pneumothorax, pneumomediastinum

Discussion

Leukocyte adhesion deficiency (LAD) is characterized by the inability of leukocytes, in particular neutrophilic granulocytes, to emigrate from the blood stream towards sites of inflammation. Infectious foci are non-purulent and may eventually become necrotic because of abnormal wound healing. LAD-I is characterized by the absence of the beta-2 integrins CD 11 and CD 18 on leukocytes. The prominent clinical feature of these patients is recurrent bacterial infections, primarily localized to skin and mucosal surfaces. Sites of infection often progressively enlarge, and they may lead to systemic spread of the bacteria. Infections are usually apparent from birth onward, and a common presenting infection is omphalitis with delayed separation of the umbilical cord. The most frequently encountered bacteria are Staphylococcus aureus and Gram-negative enteric organisms, but fungal infections are also common. The absence of pus formation at the sites of infection is one of the hallmarks of LAD I. Failure of neutrophils to bear the β2-integrins leads to inability to migrate to sites of inflammation outside of the lung because of their inability to adhere firmly to surfaces and undergo transendothelial migration. Failure of the CD11/CD18–deficient neutrophils to undergo transendothelial migration occurs because the β2-integrins bind to intercellular adhesion molecules 1 (ICAM-1) and 2 (ICAM-2) expressed on inflamed endothelial cells. The neutrophils that do arrive at inflammatory sites in the lungs by CD11/CD18-independent processes fail to recognize micro-organisms coated with the opsonin complement fragment iC3b, which is an important stable opsonin formed by the cleavage of C3b by C3b inactivator. Other neutrophil functions such as degranulation and oxidative metabolism normally triggered by iC3b binding are also diminished, and are markedly compromised in neutrophils from patients with LAD-1, resulting in impaired neutrophil function and high risk for serious and recurrent bacterial infections. The diagnosis of LAD-1 is established most readily by flow cytometric measurements of surface CD11b in stimulated and unstimulated neutrophils using monoclonal antibodies directed against CD11b. Assessment of neutrophil and monocyte adherence, aggregation, chemotaxis, and iC3b-mediated phagocytosis generally demonstrates striking abnormalities that directly correspond to the molecular deficiency. Delayed-type hypersensitivity reactions are normal, and most individuals have normal specific antibody synthesis. In any infant male or female with recurrent soft tissue infection, and a very high leukocyte count, the diagnosis of LAD I should be considered. The diagnosis is even more suggestive if a history of delayed separation of the umbilical cord is present. To confirm the diagnosis, absence of α and β subunits of the β2-integrin complex must be demonstrated. This can be accomplished with the use of the appropriate CD11 and CD18 monoclonal antibodies by flow cytometry. The optimal treatment for moderate LAD1 is unclear; and only stem cell transplantation can lead to cure.

Pyoderma gangrenosum (PG) is an uncommon condition characterized by recurrent sterile, inflammatory skin ulcers. Commonly, PG occurs in the context of inflammatory bowel disease or rheumatic, hematologic, or immunologic disorders.

Review of literature revealed very few cases of LAD with pyoderma gangrenosum.

In 1990, three siblings with LAD who developed cutaneous necrosis-resembling pyoderma gangrenosum were reported.[2]

In 1998, a 5-year-old girl with necrotic skin ulcers resembling pyoderma gangrenosum and a persistent circulating neutrophilia was reported. Investigation revealed a complete absence of CD11a/CD18 b2 integrins confirming the diagnosis of LAD type 1.[3]

The latest case report in 2010 is an 11-year-old boy with a longstanding history of recurrent pyoderma gangrenosum diagnosed with LAD Type I.[4] There has not been a single case report from India of LAD 1 with pyoderma gangrenosum.

In summary, we observed a patient with moderate LAD1 presenting with a longstanding history of recurrent PG and atrophic scarring, who succumbed to an overwhelming systemic infection. The diagnosis of LAD1 should be considered in all patients with unexplained skin ulcers, even in the absence of serious infections.[5-7] Clinicians should be careful in making a diagnosis of idiopathic PG and consider LAD1 in the differential diagnosis.

What is new?

The diagnosis of LAD1 should be considered in all patients with unexplained skin ulcers, even in the absence of serious infections. Clinicians should be careful in making a diagnosis of idiopathic PG and consider LAD1 in the differential diagnosis.