Craniofrontonasal syndrome is a rare dysostosis syndrome with an unusual pattern of X-linked inheritance, because males are usually not or less severely affected than females. Previously, a CFNS locus has been localised in Xp22. We report on a haplotype analysis in a German CFNS family, mapping the CFNS locus to the pericentromeric region of the X chromosome. This discrepancy can be explained by locus heter- ogeneity. Furthermore, random X inactivation could be demonstrated in affected females. The most plausible interpretation for this unusual pattern of X-linked inheritance is metabolic interference. Consequently, we propose that the CFNS gene escapes X inactivation.

Familial adenomatous polyposis (FAP) is an autosomal dominant condition leading to the development of multiple colorectal polyps and other features. Intrafamilial variation in phenotype is known to occur in FAP; despite carrying the same causing mutation in the APC gene, disease expression may considerably differ in affected individuals, likely due to the existence of modifier genes. Several lines of evidence suggest the cyclooxygenase‐2 (COX‐2) gene to be a candidate modifier in FAP. Since COX‐2 appears to be expressed in tissues prone to be affected in FAP, it might influence the occurrence of extracolonic manifestations in this disorder. Herein, we investigated whether alterations in the COX‐2 gene are involved in the development of extracolonic polyps and extragastrointestinal features. Mutational analysis using single‐strand conformation polymorphism (SSCP) in 130 members of a FAP family displaying strong phenotype variation revealed 3 polymorphic sites within the coding region of the COX‐2 gene. None of these allelic variants, however, segregated with a particular disease phenotype. In addition, expression analysis was performed in 31 family members with representative phenotypes. Neither of the two polymorphisms detected within the COX‐2 promoter was associated with a given phenotype nor was there a significant difference in quality or quantity of COX‐2 mRNA in lymphocytes as measured by reverse transcription‐ and real time quantitative reverse transcription PCR (RT‐PCR and TaqMan). In conclusion, germline alterations in the COX‐2 gene are unlikely to account for the development of extracolonic disease in FAP patients. Int. J. Cancer 87:812–817, 2000. © 2000 Wiley‐Liss, Inc.

We present the case of a 74-y-old HIV-negative female who suffered simultaneously from multiple opportunistic infections and a Klebsiella pneumoniae sepsis during high-dose steroids for giant cell arteritis. The patient was treated with a purine analog due to hairy cell leukaemia 10 y previously. Purine analog therapy can lead to long lasting defects in cell-mediated immunity. In these patients, treatment with steroids should be closely monitored with CD4 counts.

Familial adenomatous polyposis (FAP), an autosomal dominantly inherited colorectal cancer predisposition syndrome, displays considerable inter-and intrafamilial phenotypic heterogeneity, which represents a major problem in genetic counselling of APC mutation carriers. The Min mouse model indicated a putative disease modifier locus on chromosome 4, which is syntenic to human chromosome 1p35-36. This finding was subsequently supported by parametric and nonparametric linkage analyses in FAP families, however, without identifying functional variants in candidate genes. Recently, germline mutations in the baseexcision repair gene MYH (1p33 -34) have been described in patients with multiple adenomas, pointing to a possible role as disease modifier in FAP. Here, we present critical reassessment of one of the largest FAP kindreds published, which was previously used in linkage mapping of 1p35-36. In this family, all affected members harbour the same APC germline mutation (5945delA), but display marked phenotypic variability, in particular regarding the occurrence of extracolonic disease that segregates in several branches of the family tree. Using updated clinical information, additional mutation carriers and polymorphic markers, fine mapping of the critical region as well as mutation analysis of the MYH gene were performed. These investigations allowed us to significantly exclude (i) the 1p33 -36 region as a modifier locus and (ii) MYH as a modifier gene for extracolonic disease in this FAP kindred. Our results do not eliminate 1p33 -36 from suspicion in other families, but clearly indicate that in our family linkage analysis of further putative candidate regions is necessary to identify a disease modifier locus in FAP.