Multiple pilomatricomas with somatic CTNNB1 mutations in children with constitutive mismatch repair deficiency

Abstract

Constitutional mismatch repair deficiency (CMMR-D) due to biallelic germline mutations in one of four mismatch repair genes causes a childhood cancer syndrome characterized by a broad tumor spectrum including hematological malignancies, and brain and Lynch syndrome-associated tumors. Herein, we report three children who had in addition to CMMR-D-associated malignancies multiple pilomatricomas. These are benign skin tumors of hair matrical differentiation frequently associated with somatic activating mutations in the ß-catenin gene CTNNB1. In two of the children, the diagnosis of CMMR-D was confirmed by the identification of biallelic germline PMS2 mutations. In the third individual, we only found a heterozygous germline PMS2 mutation. In all nine pilomatricomas with basophilic cells, we detected CTNNB1 mutations. Our findings indicate that CTNNB1 is a target for mutations when mismatch repair is impaired due to biallelic PMS2 mutations. An elevated number of activating CTNNB1 alterations in hair matrix cells may explain the development of multiple pilomatricomas in CMMR-D patients. Of note, two of the children presented with multiple pilomatricomas and other nonmalignant features of CMMR-D before they developed malignancies. To offer surveillance programs to CMMR-D patients, it may be justified to suspect CMMR-D syndrome in individuals fulfilling multiple nonmalignant features of CMMR-D (including multiple pilomatricomas) and offer molecular testing in combination with interdisciplinary counseling.

Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort

“…Heterogeneous descriptions have been provided for the cutaneous phenotype of CMMRD10 28 and this study suggests that common dermatological features at presentation combine widespread or segmental CALMs and hypopigmented macules. Congenital naevi are less common, as well as pilomatricomas, rare non-malignant skin tumours unrelated to NF1 29. As previously reported,28 30 cutaneous abnormalities were absent in rare cases in this series.…”

A novel germline POLE mutation causes an early onset cancer prone syndrome mimicking constitutional mismatch repair deficiency

“…In support of this notion, it was shown that distinct pilomatricomas occurring in a single CMMRD patient resulted from different activating CTNNB1 (ß-Catenin gene) mutations. This suggests that certain genes may be targeted repeatedly by independent somatic mutational events in CMMRD patients [14]. Accordingly, the constitutional polymerase proofreading defect may explain the occurrence of these features in our patient.…”

Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘Care for CMMRD’ (C4CMMRD)

“…In two patients with genetically confirmed CMMRD syndrome, multiple pilomatricomas were reported. The authors proposed that the presence of multiple pilomatricomas that is seen very rarely in otherwise healthy individuals should raise a suspicion for an underlying MMR repair defect when observed in a paediatric cancer patient 28. Of note, there may also be an association of multiple pilomatricomas with MUTYH-associated polyposis,29 a polyposis syndrome that has certain phenotypical and patho-mechanistic overlap with CMMRD since both recessively inherited tumour predisposition syndromes are caused by DNA repair defects leading to attenuated polyposis although usually in different age groups.…”