Prevalence of CMMRD in NF1/SPRED1 Mutation Negatives

Constitutional mismatch repair deficiency (CMMRD) is a rare inherited condition. Individuals with CMMRD have an extraordinarily high risk to develop a malignant tumor in childhood or adolescence. Nearly all known CMMRD patients developed a malignancy within the first three decades of life - most often in (early) childhood. Since early cancer detection improves the chances to survive, these patients should be included in intensive cancer surveillance protocols from early childhood on. Typically patients are diagnosed with CMMRD only after they develop the first malignant tumor. But, already before the onset of the first malignant tumor children with CMMRD may have clinical signs which may serve as a signpost of this severe condition. CMMRD patients often show skin patches of milk coffee-like color, termed café au lait maculae (CALM), which are typical for a different inherited condition named neurofibromatosis type 1 (NF1). NF1, which is much more frequent than CMMRD, also leads to tumor development, but NF1 tumors are usually benign and for NF1 children different, less rigorous, tumor surveillance programs are adequate. A child with >5 CALM is suspected to have NF1. However, if this diagnosis cannot be confirmed by identification of the causative genetic alteration (NF1-mutation), CMMRD is one possible, although presumably rare, alternative (= differential) diagnosis. Therefore, human geneticists and pediatricians are discussing, whether these children should be tested for CMMRD. Diagnosing CMMRD in this situation would allow appropriate cancer surveillance protocols to be offered to these patients before they develop the first malignant tumor. However, CMMRD testing in this situation may also cause difficulties. Genetic testing may for instance render an ambiguous result, which can neither confirm nor rule out CMMRD. Such a result would create great uncertainty about the appropriate management of the patient. It would not be clear whether intensified cancer surveillance, that may be very stressful for the patient and the family, should be applied or not. Hence, when evaluating the benefits of presymptomatic (with respect to tumor onset) CMMRD testing they must be weighted against such potential disadvantages which fall more into weight if the chances to identify CMMRD in a patient and consequently achieving a benefit for the patient are low. But currently the frequency of CMMRD patients among suspected NF1 patients without a causative NF1 mutation is unknown. It is the aim of this project to acquire a reliable estimation on the frequency of the differential diagnosis CMMRD in children with NF1 signs in whom the diagnosis NF1 cannot be confirmed genetically. This information is also needed for appropriate genetic counseling of at risk children and their parents.

Constitutional mismatch repair deficiency (CMMRD) is a rare genetic/inherited condition that confers an extraordinarily high risk for cancer already in childhood and adolescence. Individuals with this condition need to be include in intensive cancer surveillance programs that should preferentially start before the onset of the first cancer. Individuals with CMMRD often have signs, such as café au lait spots (CALS) on the skin, which are reminiscent of neurofibromatosis type 1 (NF1, a genetic condition that is much more frequent than CMMRD. Individuals with NF1 also have a higher risk of certain tumors, but these are usually benign and children with NF1 need less intensive surveillance than children with CMMRD. Children with >5 CALS are suspected to have NF1. However, if this diagnosis cannot be confirmed by identification of a causative genetic alteration (mutation) in the NF1 gene, then it is possible that the child has CMMRD. Currently international consortia of pediatricians and geneticists discuss whether all NF1 children lacking a causative NF1 mutation should be tested for CMMRD. But, this bears also potential risks, such as a high level of anxiety in the patient and the family as well as a genetic testing result that does not give a definite answer whether the child has CMMRD or not and, hence, causes uncertainty regarding the appropriate management of these children. When balancing out the advantages over the risks of testing for CMMRD in suspected NF1 children without a NF1 mutation, the risks will bear more weight when the frequency of CMMRD and, hence, the chances to identify CMMRD, in these patients is low. Therefore, the primary aim of this project was it to get a reliable estimation of the frequency of CMMRD in these children. To answer this question a large number (>700) of gDNA samples of these children were anonymized and retrospectively tested for CMMRD. We showed that only 0.41% (3/735) of these children had CMMRD. This information has important implications. First, clinical geneticists and other clinicians have now reliable numbers at hand for genetic counseling of such children and their parents. Furthermore, these empirical data confirm previous prevalence estimations on which the Care for CMMRD (C4CMMRD) consortium based consensus guidelines that advocate CMMRD testing of preselected patients rather than offering reflex testing to all suspected NF1 children lacking a causative NF1 mutation. Hence, our findings show that these guidelines are based on valid data. The next step should now be to evaluate whether the criteria proposed by the C4CMMRD guidelines for the preselection of such children for CMMRD testing select indeed those children in whom the advantages outweigh the risks of CMMRD testing in this situation because the detection rate of CMMRD is substantially higher than 0.41%.