The authors describe five patients (including a mother and her son) who had a multidimensional illness comprised of recurrent infections, rash, arthritis/vasculitis, hepatosplenomegaly, and growth retardation in infancy and childhood (Table).  Although these findings were consistent with zinc deficiency, the patients had marked hyperzincemia due to its binding to greatly elevated amounts of a zinc-binding protein called calprotectin. Calprotectin is a calcium and zinc binding protein complex of two S100 plasma proteins termed S100A8 and S100A9 (also termed proteins MRP8 and MRP14, respectively).  It is present in the cytosol of phagocytes and is released into plasma as phagocytic neutrophils are destroyed.  In these patients, plasma zinc concentrations were 5-10 times higher than the upper normal range (18 µmol/L), while calprotectin concentrations were 1000 fold greater than the upper normal value (850 µg/L), suggesting that free plasma zinc concentrations were likely to be low.  Individual patients were anemic, thrombocytopenic, and had low numbers of monocytes and B lymphocytes.  Chromatographic analysis of S100A8 and S100A9 proteins was normal, suggesting no major mutations or post-translational modifications of calprotectin.  Since there was no evidence of increased neutrophil turnover rate, the investigators hypothesized: (1) that the increased plasma concentrations of calprotectin reflected its decreased rate of degradation; (2) that the patients were zinc deficient because of the high affinity of calprotectin for zinc; and (3) that calprotectin itself may have been cytotoxic to neutrophils and other tissues.

 

Sampson B, et al. Lancet 2002;360:1742-1745.

 

First Editor’s Comment: The new syndrome comprises patients with an apparent "functional zinc deficiency" despite high plasma concentrations of this element.  Although "free zinc" concentrations were not measured, they were thought to be low.  In addition, the authors did not report the effects of a trial of therapy with supplemental zinc in these subjects.  Thus, the hypothesis regarding "functional zinc deficiency" remains unproven.  Since calprotectin is a calcium binding protein, it would have been of interest to report total and ionized calcium values in these patients.

 

Zinc deficiency may be congenital or acquired.  Acrodermatitis enteropathica (OMIM 201100) is an autosomal recessively transmitted disease characterized by bullous lesions of the skin, alopecia, diarrhea, and growth failure with hypozincemia.  Administration of supplemental zinc ameliorates these abnormalities.  Approximately 50% of patients with acrodermatitis enteropathica have a loss-of-function nonsense or missense mutation in SLC394A (Solute Carrier Family 39 [Zinc Transporter], Member 4) encoding a renal- and intestine-specific transmembrane zinc transporter protein (OMIM 607059, chromosome 8q24.3).  Zinc deficiency may be acquired due to dietary deficiency, decreased absorption due to co-ingestion of zinc-binding materials such as clay or phytates, malabsorption as in patients with chronic inflammatory bowel disease, or excessive excretion as in patients with sickle cell disease and hyperzincuria.

 

Allen W. Root, MD

 

Second Editor’s Comment: I am puzzled by the possibility of copper deficiency in these patients.  The clinical picture and the anemia and leucopenia are typical of it. A deficit of this mineral would likely result in a deficiency of Ca/Zn SOD (super oxidase desmutase) though I do not know of studies of its effects on calprotectin.

 

Fima Lifshitz, MD

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