Correspondence on “Neurocutaneous Syndromes and Brain Tumors”

Abstract

We read with interest a recent review on neurocutaneous disorders associated with brain tumors by Ullrich,¹ which focused on neurofibromatosis 1, neurofibromatosis 2, schwannomatosis, tuberous sclerosis, Von Hippel Lindau, and nevoid basal cell carcinoma syndrome. However, no mention was made of the constitutional mismatch repair deficiency syndrome, which is an important cause of neurocutaneous features and brain tumors in childhood.^2,3

Heterozygous germline mutations in any of the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2, cause Lynch syndrome, an autosomal dominant cancer predisposition syndrome for colorectal, endometrial, and other adult cancers. When both spouses have Lynch syndrome, their children will have a 1:4 risk of inheriting biallelic mismatch repair gene mutations. These cause constitutional mismatch repair deficiency syndrome, a severe recessively inherited cancer syndrome with a broad tumor spectrum, including mainly brain tumors, hematologic malignancies, and colon cancer in childhood and adolescence.

Many constitutional mismatch repair deficiency children also present with café au lait spots and axillary freckling and are very often misdiagnosed as having neurofibromatosis type 1. Accurate and early diagnosis is vital because in constitutional mismatch repair deficiency syndrome, the brain tumors are malignant unlike the usually low-grade gliomas seen in neurofibromatosis 1, and include high-grade gliomas, supratentorial primitive neuroectodermal tumors, and medulloblastoma. Also, neurofibromatosis 1 is not in any way associated with bowel cancer.

Surveillance protocols to enable the detection of presymptomatic malignancies have been proposed for children with constitutional mismatch repair deficiency syndrome including brain magnetic resonance imaging (MRI) every 6 to 12 months starting at the age of 2 years.^4,5

Because pediatricians and pediatric neurologists are often the first to see patients with this syndrome, they should be aware of this entity and take an accurate family history. This is especially important for physicians in areas where founder mutations and/or consanguinity are prevalent. The correct diagnosis of these patients will allow identification of all family members at risk either for Lynch syndrome or constitutional mismatch repair deficiency syndrome, implementation of surveillance and prenatal or preimplantation gestational diagnosis as options for these families, as well as optimal treatment protocols.

Helen Toledano, MB, ChB Department of Pediatric Oncology, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Inbal Barnes-Kedar, MSc The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel Hagit N. Baris, MD The Genetics Institute, Rambam Health Care Campus, Haifa, Israel Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

References

Ullrich

. Neurocutaneous syndromes and brain tumors [published online ahead of print October 12, 2015]. J Child Neurol. pii:0883073815604220.

Baris

Barnes-Kedar

Toledano

. Constitutional mismatch repair deficiency in Israel: high proportion of founder mutations in MMR genes and consanguinity. Pediatr Blood Cancer. 2016;63(3):418–427.

Wimmer

Kratz

Vasen

HFA

; EU-Consortium Care for CMMRD (C4CMMRD). Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium “Care for CMMRD” (C4CMMRD). J Med Genet. 2014;51(6):355–365.

Durno

Aronson

Tabori

. Oncologic surveillance for subjects with biallelic mismatch repair gene mutations: 10 year follow-up of a kindred. Pediatr Blood Cancer. 2012;59(4):652–656.

Vasen

Ghorbanoghli

Bourdeaut

; EU-Consortium Care for CMMR-D (C4CMMR-D). Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D). J Med Genet. 2014;51(5):283–293.