Background:Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent skin infections with abscesses, recurrent pneumonias with pneumatoceles, and immunoglobulin E levels of >10 times the upper limit of normal.Case:The patient described herein had a classic case of signal transducer and activator of transcription 3 (STAT3) deficiency associated with HIES diagnosed several years before this particular presentation. He demonstrated extraimmune manifestations of the disease as well, including characteristic facies and a history of skeletal fractures. In addition, the patient had several distinct episodes of idiopathic pancreatitis for which a full gastrointestinal workup had been performed. STAT3 mutation was confirmed by genotyping at the time of diagnosis of HIES.Conclusions:STAT3, a mammalian protein that regulates cell growth, survival, and differentiation, has been linked to human pancreatic carcinogenesis as well as the above-mentioned immune deficiency. Mouse studies demonstrated that genetic ablation of STAT3 exacerbates the course of acute pancreatitis, whereas normal pancreatic STAT3 seems to have a protective effect against necrotizing pancreatitis. An association between STAT3 mutations and pancreatitis has not yet been revealed in humans. Here we describe a case of acute pancreatitis that presented in a patient with STAT3 mutation.
RATIONALE: About 20% of patients with ADA deficiency have a ''delayed-onset'' presentation beyond the first year of life, with fewer infectious complications than those with ADA deficiency and SCID. A 4year-old girl presented with a history of recurrent infections, panhypogammaglobulinemia and CD4 lymphopenia but normal CD8 counts. Low copy numbers of CMV and adenovirus DNA were detected in the blood. METHODS: ADA activity was measured in erythrocytes and sorted T cells. Genomic DNA was utilized to sequence the ADA gene, and an identified missense variant was sequenced in sorted peripheral blood cell subpopulations. RESULTS: ADA enzyme activity in RBCs was 0.1 nmol/h/mg (reference range 63 +/-41). Genomic DNA showed two known mutations: c.955-959delGAAGA and c.467 G>A, which predicts the R156H substitution. ADA activity in sorted CD8 T cells was normal. Wild-type c.467 G was present in more than 50% of sequences from CD8+ T cells, indicating a somatic cell reversion. IgG and ADA replacement resulted in clinical improvement. CONCLUSIONS: R156H is among several ADA missense mutations that cause incomplete loss of ADA activity, leading to delayed-onset disease with less severe infectious complications. Somatic reversion to WT has also been associated with a milder phenotype. In our patient, functional CD8 T cells in which reversion of R156H to WT had occurred may have resulted in the partial control of viral infections, and specific antigenic stimulation may in turn have led to expansion of the reverted CD8 T cells. Additional work will attempt to identify the developmental stage where reversion occurred and the functional consequences.
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