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We read with special interest the article of Busiello and colleagues in Blood. [1][1] They described atypical features of familial hemophagocytic lymphohistiocytosis (FHLH) in a patient/family presenting 2 different perforin gene alterations: an already known homozygous A91V and a novel heterozygous

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 disease-free interval during which biochemical or immunologic alterations may be not evident, thus implying a role for interfering factors. (Blood. 2004;103:4610-4612)

Summary Familial haemophagocytic lymphohistiocytosis (FHLH) is a heterogeneous autosomal recessive disorder characterized by hyperactivation of monocytes/macrophages. Perforin (PRF1) gene alterations have been documented in 40% of patients with FHLH. Although several mutations have been identified, a clear correlation between the individual molecular alteration and the phenotypic expression of the disease is still unclear. In particular, the role that the A91V substitution plays in the pathogenesis of the disease is still controversial. In the effort to make a conclusive remark to this issue, we here report on the frequency of the A91V mutation in a group of unrelated healthy families obtained from the ‘Centre d’Etude du Polymorphisme Humain’ (CEPH), which are considered representative of the worldwide population. This frequency was compared to that observed in FHLH patients recruited through the Italian National Registry. The frequency in CEPH healthy subjects is 3.7%, thus indicating that the alteration represents a polymorphism. However, the frequency of this alteration in FHLH patients associated with PRF1 mutation is much higher than that observed in controls (26.2%, P = 0.0002), suggesting that the alteration is an important genetic susceptibility factor.

4 páginas, 1 figura, 1 tabla., Genetic alterations of the FOXN1 transcription factor, selectively expressed in thymic epithelia and skin, are responsible in both mice and humans for the Nude/SCID phenotype. The first described human FOXN1 mutation was a C792T transition in exon 5 resulting in the nonsense mutation R255X, and was detected in two probands originated from a small community in southern Italy. In this community, four additional children affected with congenital alopecia died in early childhood because of severe infections. In this study, we report on the screening for this mutation in 30% of the village population. This analysis led us to identify 55 heterozygous carriers (6.52%) of the R255X mutation out of 843 inhabitants screened. A genealogical study revealed that these subjects, belonging to 39 families, were linked in an extended 7-generational pedigree comprising 483 individuals. Through the archival database a single ancestral couple, born at the beginning of the 19th century, was identified. To confirm the ancestral origin of the mutation we genotyped two microsatellite markers, D17S2187 and D17S1880, flanking the FOXN1 gene on chromosome 17. The three haplotypes identified, 3/R255X/3, 3/R255X/2 and 3/R255X/1, are consistent with a single ancestral origin for the mutation R255X., This work was supported by the Grants “Ministero della Salute - Roma and Regione Campania, Legge 502”, MIUR-PRIN 2002 and Telethon #E0934.

Severe combined immunodeficiency (SCID) is a heterogeneous group of disorders characterized by a severe defect of both T- and B-cell immunity, which generally require allogeneic bone marrow transplantation (BMT) within the first years of life. We previously reported a patient affected with an X-linked SCID due to L183S hemizygous missense gamma chain mutation, whose severe short stature was due to a peripheral growth hormone (GH) hyporesponsiveness associated to abnormal GH receptor (GH-R) signal transduction. In this study, we report the effect of BMT on the GH-R/insulin-like growth factor I (IGF-I) axis. After BMT, the patient showed a significant improvement in linear growth and normalization of basal- and GH-stimulated IGF-I values, which paralleled a fully competent immunological reconstitution. This suggests that cells derived from the hematopoietic stem cell may exert an unexpectedly significant role in producing IGF-I. This may also suggest that stem cell-based therapies may be useful for the correction of non-hematopoietic inherited disorders, such as those of GH-R/IGF-I axis.