Background and Aims

Activated phosphoinositide 3-kinase delta (PI3K) syndrome (APDS) is characterized by variable humoral and cellular defects, recurrent infections, lymphoma, autoimmune features, and growth and developmental delay.

Sweet syndrome, or acute febrile neutrophilic dermatosis, is a rare inflammatory skin condition. About half of cases have an underlying systemic disorder, mainly malignancies and autoinflammatory conditions. It has only been sporadically reported in patients with immunodeficiency.

We report a boy with APDS presenting as a combined immunodeficiency and Sweet syndrome.

Methods

Immunological tests, skin biopsies and PID gene panel analysis were performed.

Results

A boy, currently 16 years old, suffered from recurrent bacterial infections since the age of 3 years. He also developed bronchiectasis, lymphadenopathies and splenomegaly. Immunological work-up revealed low IgG2, reduced polysaccharide antibody responses, monocytopenia and T, B and NK lymphopenia. Recently, we identified a PIK3CD mutation causing APDS.

Remarkably, since 5 years of age, he had recurrent painful erythematous nodules and plaques on his limbs and abdomen, accompanied by fever and elevated inflammatory markers. Biopsies showed a dense neutrophilic infiltrate confirming the diagnosis of Sweet syndrome. Acute episodes responded well to systemic corticosteroids. Up till now, he requires dapsone maintenance therapy to prevent relapse.

Conclusions

To our knowledge, this is the first report of an APDS patient with Sweet syndrome. The pathophysiology of Sweet syndrome is unclear but involves activation of innate inflammatory signaling. Previous studies have demonstrated a role for PI3K/Akt signaling in NLRP3-inflammasome activation. Together, this suggests dysregulation of inflammasome activation in APDS patients, implying potentially therapeutic effects of IL-1 inhibition.

Background and Aims

Germline heterozygous GATA2 mutations causing GATA2 deficiency are characterized by a broad phenotypic spectrum including cytopenias, severe bacterial, viral and nontuberculous mycobacterial infections, myelodysplasia and myeloid leukemias, pulmonary alveolar proteinosis, and lymphedema. The only curative treatment is allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Based on our experience with three cases, we address the difficulties often faced by clinicians in this extraordinary syndrome that was only identified in 2011.

Methods

Hematological, immunological and genetic analyses were performed.

Results

Three GATA2-deficient patients were diagnosed in our center. All had MDS/AML and low monocyte, B-cell, NK-cell and dendritic cell counts. Two patients also had severe infections. Unfortunately, there are no guidelines regarding the optimal timing, conditioning regimen, donor source and antimicrobial prophylaxis for HSCT. Patient 1, a female, is doing well under immunoglobulin replacement therapy nine years after chemotherapy for AML, without HSCT. Patients 2 and 3, males, both underwent allo-HSCT because of life-threatening infections and MDS, but using different conditioning regimens and donor types. Patient 2 suffered from severe chronic GVHD and died four years post-transplant from ischemic heart disease. Patient 3 was transplanted using more intensive non-myeloablative conditioning, and is currently doing well two years post-transplant.

Furthermore, mutation analysis of GATA2 turned out to be technically cumbersome. In one patient, intensive screening for mutations was negative and was only found through array-CGH.

Conclusions

Although there are still challenges in clinical practice that need to be overcome, increasing experience in transplanting these patients has gained insight on optimal donor and stem cell source and conditioning.

Background and Aims

A 5-year-old girl presented with three episodes of otomastoiditis caused by Candida species. The last episode was complicated with persistent Staphylococcus Aureus cervical lymph node abscess. She was treated with transtympanic drains, mastoidectomy and long-term antibiotics and antifungal therapy, as well as drainage and curettage for the cervical abscess.

Methods

Immunological work-up consisted of standard blood analysis, lymphocyte proliferation test and respiratory burst assay. Subsequently, based on the results, genetic testing for chronic granulomatous disease (CGD) (CYBA, CYBB, NCF1, NCF2 and NCF4) and myeloperoxidase deficiency (MPO) was performed, as well as histochemical staining of leukocytes.

Results

General immunological testing was normal, except for a very weak response in the respiratory burst assay (<10% at multiple testing), suggesting CGD. However, gene testing for CGD was negative. Subsequently, MPO expression on neutrophils was absent. Analysis of the MPO gene showed a homozygous splice site mutation in intron 11 (c.2031-2A>C), producing an abnormal precursor without the enzymatic activity. Subsequent familial screening revealed the same mutation in her younger brother presenting with recurrent oral candidiasis.

Conclusions

MPO deficiency should be considered in patients with recurrent Candida infections and reduced respiratory burst. It is the most frequent congenital phagocytic cell disorder leading to an increased risk of infections with Candida and Aspergillus species. The majority of patients are asymptomatic or only exhibit minor infections, but some will develop major infections, especially in presence of concomitant diabetes mellitus. Our patient was successfully treated with a prophylactic dose of fluconazole.