Letter to the editor: mistaken inheritance.

Abstract

Dear Editor: We read with interest the recent letter to the editor written by Victoria Fretwell and Paul Rooney, regarding their 15year-old patient with reported biallelic mutations [1]. Unfortunately, there are significant errors in this report, and we are writing to highlight our findings and concerns. The authors describe a 15-year-old girl with rectal cancer who was found to have mutations in both the MLH1 and MSH6 genes. The authors incorrectly refer to this as Bbiallelic inheritance.^ Although unusual to have two mutations in two different mismatch repair genes, this is not consistent with the definition of biallelic inheritance. The definition of biallelic mutations is Bpathogenic sequence alterations, albeit not necessarily identical, present in both copies of the same gene^ [2]. The case described by Fretwell and Rooney instead has double heterozygous mutations. Biallelic mutations in mismatch repair genes results in constitutional mismatch repair deficiency (CMMRD) syndrome. CMMRD syndrome is characterized by features similar to neurofibromatosis type 1 (NF1), in addition to an increased risk for childhood onset hematologic malignancies, brain tumors, and Lynch syndrome cancers [3]. Individuals with double heterozygous mutations in mismatch repair genes are not expected to have features similar to those with CMMRD syndrome and likely have similar cancer risks as those with Lynch syndrome. A similar scenario is seen for double heterozygous mutations in BRCA1 and BRCA2, which have a similar phenotype to individuals with monoallelic BRCA1 or BRCA2mutations [4]. There is another case report of a woman with mutations in bothMLH1 andMSH6 who was diagnosed with endometrial cancer at the age of 41 years [5]. This is a typical age of diagnosis for a patient with a single MMR gene mutation. Additionally, despite the authors’ declaration, theirs is not the first case in the literature of an individual with both MLH1 and MSH6 mutations. We would also would like to highlight a few other concerns we have. One concern is that the variants found inMLH1 and MSH6were not included in this report. There is no way for the reader to determine if the MLH1 and MSH6 variants were indeed pathogenic. The authors also provide no information on whether the patient has signs of CMMRD syndrome or if microsatellite instability and/or mismatch repair immunohistochemistry tumor analyses were performed, all of which might provide insight into the etiology of this young girl’s rectal cancer. Another major disquiet is that the authors allude to making treatment decisions based on the biallelic inheritance and further allude to the girl’s imminent early death based on mistaken information. In summary, the basis of this report, biallelic inheritance, is factually incorrect. Given the erroneous and missing information presented, this case has little scientific merit as presented and leaves us with more questions and concerns, than answers.