Lymphoma, Hodgkin, X-Linked Pseudoautosomal
Description
Classic Hodgkin lymphoma is a malignancy of B-cell origin in which the neoplastic cells, known as 'Reed-Sternberg' (RS) cells, are characteristically binucleated (summary by Salipante et al., 2009). See also 236000.
InheritanceHafez et al. (1985) estimated that the heritable component of Hodgkin disease is as high as one-third. Additional evidence supporting an inherited predisposition comes from twin studies, racial-incidence patterns, and occurrences of multiplex families. Observations in a small number of affected relative pairs suggested the presence of an HLA-linked locus (Chakravarti et al., 1986), but this could account for only a minority of the familial risk observed in proband studies (Shugart and Collins, 1998).
Leri-Weill dyschondrosteosis (LWD; 127300) is a skeletal dysplasia characterized by short stature, shortened forelimbs, and distal radioulnar (Madelung) deformity. This entity had long been thought to be inherited as an autosomal disorder, presumably autosomal dominant, but was subsequently shown to be due to mutation, deletion, or other disruption of the SHOX gene (312865), which is located in the pseudoautosomal region (PAR). In the epidemiology of Hodgkin disease, an increased frequency of sex concordance among affected sib pairs has suggested pseudoautosomal linkage (see also 400021). Furthermore, Gokhale et al. (1995) reported a pair of sisters with both Hodgkin disease and LWD. There was a multigenerational, maternal history of LWD, and, in maternal relatives, a further history of Hodgkin disease without known LWD. Gokhale et al. (1995) raised the possibility that either LWD and Hodgkin disease results from a mutation deleting adjacent genes responsible for both illnesses, or that genes for the 2 diseases are linked. At the time of report by Gokhale et al. (1995), LWD was attributed to autosomal dominant inheritance.
A unique pattern of inheritance is expected from mutations in a gene in the PAR. If the locus were situated on the centromeric portion of the short-arm PAR, proximal to the invariant recombination, then the mutant allele would consistently segregate, during male meiosis, with sexual phenotype. A man could possess the mutant allele on either his X or Y chromosome. If it were on the X chromosome, then only his daughters would inherit the allele, whereas if it resided on the Y chromosome, only his sons would inherit the allele. A similar prediction pertains to loci situated on the long-arm PAR, where recombination between the X and Y chromosomes is rare. In the case of paternal inheritance of a gene situated at the telomeric boundary of the short-arm PAR, where recombination probability is 0.5, there would be no difference with a random sex distribution, and sex-discordant and sex-concordant sib pairs would be equally probable. Since the mutant allele can reside on either of a woman's X chromosomes, maternal inheritance would result in random segregation with sex. Overall, there should be a deficiency of sex-discordant, compared with sex-concordant, affected sib pairs, with the magnitude of the difference being twice as great for a recessive gene as for a dominant gene and lessening with closing proximity to the telomere. Indeed, an excess of sex-concordant sib pairs with Hodgkin disease was noted by Grufferman et al. (1977).
MappingHorwitz and Wiernik (1999) tested the hypothesis that there is a PAR-localized gene for Hodgkin disease. By first scoring recombinations dissociating sex from phenotype in individuals from pedigrees with LWD, they determined a male maximum recombination frequency of 0.405. This placed SHOX, the gene mutant in LWD, near the short-arm telomeres of the sex chromosome and supported the prediction that PAR recombination is obligatory for spermatogenesis. By inferring recombinations between Hodgkin disease and sexual phenotype in sib pairs, they predicted, for the postulated Hodgkin disease gene, a male theta (max) as high as 0.254, which placed it in proximity to SHOX. The nonparametric affected-sib-pair 'beta' model of Morton was used in the evaluation of linkage between Hodgkin disease and phenotypic sex and gave a lod score of 2.41. Using this approach, Horwitz and Wiernik (1999) reevaluated evidence for HLA linkage in Hodgkin disease in haplotyped sib pairs and found a lod score of 2.00. The resulting beta values indicated that the putative PAR-linked and HLA-linked loci account for 29% and 40%, respectively, of the heritability of Hodgkin disease in an American population. Whittemore and Shih (2000) commented on the work of Horwitz and Wiernik (1999).
Using microsatellite marker analysis and FISH, Shears et al. (2003) further studied the PAR in the family reported by Gokhale et al. (1995). Results confirmed that the 2 sibs with Hodgkin disease and LWD each harbored a maternally inherited microdeletion within the PAR, encompassing the SHOX gene, estimated to be 900 kb and located between 200 and 1,100 kb from the Xp telomere. Three genes of potential importance in Hodgkin lymphoma located within the PAR--IL3RA (308385), CSF2RA (306250), and MIC2 (313470)--were not within the deleted region in the 2 sibs. Although it was not possible to exclude haploinsufficiency due to the deletion of some unknown tumor suppressor gene, an intriguing possibility was that the PAR deletion caused a long-range position effect by downregulating expression of 1 of the above genes. MIC2 was considered a particularly strong candidate as decreased expression had been found to be associated with the generation of cells with Hodgkin and Reed-Sternberg phenotype (Kim et al., 1998).