Atypical features of familial hemophagocytic lymphohistiocytosis

Abstract

Familial hemophagocytic lymphohistiocytosis (FHLH) is a rare, rapidly progressive disorder of early childhood characterized by uncontrolled activation of T cells and macrophages. Although perforin gene mutations have been described in a proportion of patients with FHLH, the genotype/ phenotype correlation is still limited. Only a few patients with late onset clinical manifestations have been reported. The biochemical and immunologic alterations in the asymptomatic phase are not well known. We report on a family in which 2 fraternal twins both homozygous for a perforin mutation previously described as causative of the disease, markedly differed in phenotypic expression of FHLH. The twins also had a second novel heterozygous mutation. Natural killer (NK) activity was severely impaired in the patient and was normal in the asymptomatic fraternal twin. Our report highlights that FHLH may present after a long diseasefree interval during which biochemical or immunologic alterations may be not evident, thus implying a role for interfering factors. (Blood. 2004;103:4610-4612)

Development of hemophagocytic lymphohistiocytosis in triplets infected with HHV-8

“…Although certain perforin mutations may not allow for antibody reactivity, functional analysis of both subjects also demonstrated no significant NK-cell cytotoxicity, indicating that the compound heterozygous mutations result in nonexpressed or nonfunctional perforin. Similar to Busiello et al, 13 there were also phenotypic differences between each affected triplet in our study, including time of onset of disease, as well as differences in the percentage of circulating NK cells, and expression of cellular granzymes A and B. These results suggest that, despite having the same genetic mutations, there are significant polygenetic influences in the development of HLH.…”

“…There have been 2 previous reports of perforin gene mutations in twins. 13,14 Twins reported by Lipton et al 14 presented in the newborn period with symptoms consistent with HLH. Genetic analysis demonstrated a single missense mutation in the perforin gene (PRF1) in only one of the twins and their mother.…”

“…The unaffected twin reportedly demonstrated normal NK-cell activity. 13 In our study, the affected triplets presented within 12 weeks of each other following a viral prodrome. HHV-8 infection was documented by PCR amplification in both subjects using a previously published technique.…”

“…It was presumed that each twin inherited an additional genetic mutation in the perforin gene from their father; however, this point was not documented. 14 Busiello et al 13 reported on 2 fraternal twins having the same homozygous perforin mutations. Despite both twins having the same perforin mutations, only one reportedly developed HLH.…”

Immunodeficiency diagnosis: a Mondrian or Pollock scenario?

“…The logjam was broken when Towne and colleagues showed that all 3 IL-36 agonists and IL-36Ra need to be processed at one particular position (with apparently zero tolerance), close to the N-terminus of the precursor protein. 6 Once supplied to cells that have IL-36 receptors in this "polished" form, the vast functional discrepancy disappears between IL-36 and IL-1. What we still do not know is which proteases in nature can "polish" IL-36.…”