Autoimmune neutropenia of infancy: Data from the Italian neutropenia registry

Abstract

. The local Ethics Committee approved the protocol. We analyzed data from all the 159 patients admitted in the study period with suspected iron overload based on high TS (above 55% in men and 45% in women) and/or SF (> 322 ng/mL), who had undergone MRI-T2* for heart, liver, spleen, and/or pancreas iron overload and had been screened for the presence of HFE mutations by allele-specific PCR (polymerase chain reaction). The calculations of liver iron concentration (LIC) values were based on liver MRI-T2* measurements, using the Thalassemia-Tools software (Cardiovascular Imaging Solutions, London, UK).Mutations in the HFE gene were identified in 109/159 (68.6%) patients. The most common mutation in our sample was H63D, present in 91 patients (57.2%): 14 (8.8%) were homozygous, 69 (43.4%) heterozygous, and 8 (5%) compound heterozygous for C282Y/H63D. For the C282Y mutation, in contrast, only 5 patients (3.1%) were homozygous and 11 (6.9%) were heterozygous. The S65C mutation was detected in heterozygous state in 2 (2.5%) cases.All 159 patients underwent abdominal MRI-T2* and 126 underwent cardiac MRI-T2* too. Only 3 out of 126 cardiac MRIs had a positive T2* result, mild cardiac overload (T2*: 18.98, 19.14, and 19.8 ms). Of these, two patients had the H63D mutation (1 homozygous and 1 heterozygous) and one patient did not have any of the mutations studied. In the liver, 61 (38.4%) patients had iron overload (T2*: < 11.4 ms and LIC > 2.0 mg/g) of which 57 (35.8%) were light (T2*: 3.83-11.4 ms and LIC: 2.01-6.86 mg/g), and four (2.5%) moderate (T2*: 2.0-3.8 ms and LIC: 7.06-13.56 mg/g). Of these patients with liver overload, 27.9% were C282Y carriers (8.2% homozygous, 11.5% heterozygous, and 8.2% compound heterozygous C282Y/H63D), and 50.8% carried the H63D mutation (14.8% in homozygosis and 36.1% in heterozygosis). Only 12 (19.7%) patients with liver overload did not have the HFE mutation.The presence of C282Y mutation (in either homo or heterozygosis), compound heterozygous (C282/H63D), and H63D in homozygosis was significantly associated with a higher frequency of iron overload in the liver as measured by T2* (P 5 0.001). However, this was not true in patients with H63D in heterozygosis or absence of mutation (P 5 0.42), in which overload frequency was 68.4% and 29.1%, respectively.Pancreatic overload was diagnosed in 33 patients (21%), and 56 patients (35.7%) had splenic overload (Table I). The presence of the C282Y was associated with an overall higher frequency of iron overload. There was also a relatively high frequency (37.3%) of abnormal T2* values in H63D mutants both in the liver and in the spleen, and the frequency of splenic iron overload in H63D mutants was similar to that associated with the C282Y mutation.SF results were available for 152 patients. Median SF was 647 ng/mL (72-13,625), and in 138 patients (90.8%) SF was abnormally high. Overall, in 28 patients (18.2%) serum levels were higher than 1,000 ng/mL, in 80 patients (54%) they varied from 501 to 1,000 ng/mL and in 30 (20.3%) they ranged from 324...

An update on the diagnosis and treatment of chronic idiopathic neutropenia

“…A recent study of 157 pediatric patients with AIN from the Italian Neutropenia Registry (median age at onset was 0.7 years) reported results of immunological testing and bone marrow examinations in patients with AIN with a primary diagnosis based on clinical presentation and subsequent resolution of neutropenia. [24] The bone marrows in 52 of 54 patients were normal; only 2 showed a moderate decrease in myeloid cellularity. The granulocyte immunofluorescence tests (GIFT) performed in three laboratories showed a sensitivity of 62% with a single assay; repeat assay showed 82% were positive.…”

Mechanism-Based Strategies for the Management of Autoimmunity and Immune Dysregulation in Primary Immunodeficiencies

“…Autoimmune cytopenias have been described in both innate and adaptive immune deficiencies (3, 7) and may be the first sign of immune dysregulation that precedes the classical presentation of PID with recurrent or opportunistic infections (8, 9). Clinical warning signs that may prompt the clinician to consider PID at an earlier stage include: multi-lineage cytopenias, AIHA with no response to first-line therapy, persistent/chronic ITP, and AN in a patient > two years of age and/or persistent for > 24 months (10-14). …”

Autoimmune and other acquired neutropenias

“…5–10 Anti-neutrophil antibody tests have little or no diagnostic value (discussed below, under Diagnosis and Management). Common characteristics are summarized in Table 1.…”

“…Neutropenia generally presents in the first year of life (range 2–54 months), and resolves by age 2–4 years. 8–10 This form of neutropenia, the “most common” form of chronic neutropenia in childhood, is quite rare, occurring in only about 1/100,000 children per year; 11 however, many cases are probably undetected, as the asymptomatic children have no clinical indications for blood counts.…”