Manigand et al. (1964) described a brother and sister with Hodgkin disease and reviewed the literature on familial occurrence. In familial cases Vianna et al. (1974) found that the time-intervals between diagnoses were shorter than the age differences. ... Manigand et al. (1964) described a brother and sister with Hodgkin disease and reviewed the literature on familial occurrence. In familial cases Vianna et al. (1974) found that the time-intervals between diagnoses were shorter than the age differences. Also the time-intervals were shorter for relatives living together than for those living apart. These findings suggested an environmental basis for familial occurrence. On the other hand, the similarity of Rye histologic type in relatives, regardless of proximity, suggested a genetic factor in host reactivity. Fraumeni et al. (1975) described a kindred in which, in 1 sibship of 9 adults, 4 died of lymphocytic or histiocytic lymphomas and 1, a male, died of Waldenstrom macroglobulinemia complicated by adenocarcinoma of the lung. In the next generation, 1 person died of Hodgkin disease; 4 of 9 healthy persons had impaired lymphocyte transformation with phytohemagglutinin, and 3 of these had polyclonal elevation of IgM. Subsequent to the studies, adenocarcinoma of the lung developed in 1 of those with an immune defect, a woman, and her 3-year-old grandson developed lymphocytic leukemia. This was the first suggestion of a genetic or immunologic basis of lung adenocarcinoma. Grufferman et al. (1977) found a 7-fold increased risk of Hodgkin disease in sibs under 45 years of age. Twelve of 13 sib pairs were sex-concordant. The series showed an excess of nodular sclerosis type and pairs showed an excess of concordance for this type. This type may be the form most likely to have an infectious basis (Cole et al., 1968). Apparently no excess sib risk exists for Hodgkin disease diagnosed after age 45. MacMahon (1966) suggested that the cause may differ in the young and old. In general, a primarily nongenetic basis is suggested by these findings. Conte et al. (1983) studied 4 families, each with 2 cases of Hodgkin disease of the nodular sclerosis type. All 8 patients showed B18 antigen. The affected persons included father-son, brother-sister, mother-son, and father-daughter pairs. Salipante et al. (2009) studied a family in which the proband developed the nodular sclerosis type of classic Hodgkin lymphoma (CHL) at age 39 years and 2 sibs also developed nodular sclerosis-type CHL as adults. Their mother died shortly after presenting with a mediastinal tumor, compatible with CHL in terms of its location, for which she declined further evaluation.
In a family with the nodular sclerosis type of classic Hodgkin lymphoma in which affected individuals carried a t(2,3)(q11.2;p21.31) translocation that disrupted the KLHDC8B gene, Salipante et al. (2009) found that family members with the translocation expressed only ... In a family with the nodular sclerosis type of classic Hodgkin lymphoma in which affected individuals carried a t(2,3)(q11.2;p21.31) translocation that disrupted the KLHDC8B gene, Salipante et al. (2009) found that family members with the translocation expressed only about half as much KLHDC8B as those without the translocation and had correspondingly reduced expression of protein. Salipante et al. (2009) then analyzed the KLHDC8B gene in 52 probands from families with 2 or more individuals with CHL and identified a SNP in the 5-prime UTR (28C-T; 613169.0001) that was present in probands from 3 (5.8%) of 52 families compared with 4 (1.3%) of 307 controls (odds ratio, 4.64; 95% confidence interval, 1.01-21.4). The variant segregated with disease and was associated with a reduction in translation of mRNA. In addition, Reed-Sternberg cells from 1 of 3 informative sporadic CHL patients showed loss of heterozygosity for markers within and flanking the KLHDC8B gene on chromosome 3p21.31. Lamprecht et al. (2010) found that Reed-Sternberg cells in Hodgkin lymphoma demonstrated upregulation of CSF1R (164770) and CSF1 (120420) mRNA and constitutive activation of CSF1R, which correlated with increased proliferation of the Reed-Sternberg cells. Non-Hodkgin cell lines did not express either gene, suggesting that the expression in Reed-Sternberg cells was aberrant. Analysis of CSF1R transcripts in Reed-Sternberg cells showed use of an alternative transcription start site located about 6.2-kb upstream of the normal myeloid transcription start site: this sequence corresponded to a long terminal repeat (LTR) of the MaLR THE1B family. LTRs derived from ancient retroviral infections have accumulated in the mammalian genome, and mammalian organisms have devised a number of surveillance mechanisms to silence these elements early in development, usually by DNA methylation. The LTR region was found to contain a number of putative binding sites for transcription factors (i.e., NFKB; 164011) that were expressed in the Reed-Sternberg cells. Further studies indicated that the LTR is normally repressed by epigenetic methylation, and that Reed-Sternberg cells had lost this methylation. In addition, nearly all Reed-Sternberg cells studies had lost expression of the transcriptional repressor CBFA2T3 (603870). LTR-driven CSF1R transcripts were also found in anaplastic large cell lymphoma. Lamprecht et al. (2010) suggested that inhibition of CSF1R signaling may be of therapeutic value in Hodgkin lymphoma.
Ferraris et al. (1997) quoted an estimate of 4.5% as the proportion of all cases of Hodgkin disease represented by familial Hodgkin disease. They reviewed 28 articles on familial Hodgkin disease, published between 1972 and 1995, with detailed ... Ferraris et al. (1997) quoted an estimate of 4.5% as the proportion of all cases of Hodgkin disease represented by familial Hodgkin disease. They reviewed 28 articles on familial Hodgkin disease, published between 1972 and 1995, with detailed analysis of data from 18 papers, reporting on 328 patients. The male-to-female ratio was 1.5, similar to that reported for sporadic Hodgkin disease. A significant difference was found between sporadic and familial Hodgkin disease in the age at diagnosis: only 1 major peak between 15 and 34 years was present in the group of patients with familial Hodgkin disease. For the sporadic disease, the age of onset is characteristically bimodal, with a peak in the late twenties and another after the age of 50. A notable exception is Japan, where the young-adult incidence peak of Hodgkin disease is barely detectable.