Abstract Lynch syndrome, the most common inherited colorectal cancer syndrome in adults, is an autosomal dominant condition caused by heterozygous germ-line mutations in DNA mismatch repair (MMR) ...genes MLH1, MSH2, MSH6 and PMS2 . Inheriting biallelic (homozygous) mutations in any of the MMR genes results in a different clinical syndrome termed biallelic mismatch repair deficiency (BMMR-D) that is characterised by gastrointestinal tumours, skin lesions, brain tumours and haematologic malignancies. This recently described and under-recognised syndrome can present with adenomatous polyps leading to early-onset small bowel and colorectal adenocarcinoma. An important clue in the family history that suggests underling BMMR-D is consanguinity. Interestingly, pedigrees of BMMR-D patients typically show a paucity of Lynch syndrome cancers and most parents are unaffected. Therefore, a family history of cancers is often non-contributory. Detection of BMMR-D can lead to more appropriate genetic counselling and the implementation of targeted surveillance protocols to achieve earlier tumour detection that will allow surgical resection. This review describes an approach for diagnosis and management of these patients and their families.
A novel cancer syndrome associated with biallelic mismatch repair (MMR) mutations has been described recently. Patients presenting with childhood-onset gastrointestinal (GI) cancers may carry ...biallelic MMR mutations and have a distinct phenotype from classic Lynch syndrome. The aim of this study was to characterize patients with GI small bowel and/or colorectal cancers (CRCs) who have germline biallelic MMR mutations.
A search of a Canadian GI cancer registry and literature review to identify patients with biallelic MMR was conducted.
The database identified 237 patients with intestinal cancer diagnosed before the age of 35 years. Five (2.1%) patients had biallelic MMR mutations. Overall, 32 individuals, from 29 families, with biallelic MMR gene mutations and GI cancers were identified by the registry and literature review. Among the 29 patients with CRCs, the mean age of first cancer diagnosis was 16.4 years (range: 5-28). More than one-third of patients had multiple colorectal adenomas (>10 polyps). Six individuals with biallelic MMR gene mutations have been reported with small bowel adenocarcinoma (mean age 20 years (range: 11-41)). Café-au-lait (CAL) macules were reported in 72% and, based on mutation analysis, consanguinity was suspected in 52% of kindred. Of the 29 kindred, 19 (66%) had PMS2 mutations, 6 (21%) had MSH6 mutations, 3 (10%) had MLH1 mutations, and 1 (3%) had MSH2 mutation.
Biallelic MMR mutations are an underrecognized cause of small bowel and colonic cancers in children and young adults. This distinct phenotype includes multiple adenomatous polyps and CAL skin lesions. It is important to identify such patients, so that families can be referred for genetic testing and counseling.
The US Multi-Society Task Force on Colorectal Cancer, with invited experts, developed a consensus statement and recommendations to assist health care providers with appropriate management of patients ...with biallelic mismatch repair deficiency (BMMRD) syndrome, also called constitutional mismatch repair deficiency syndrome. This position paper outlines what is known about BMMRD, the unique genetic and clinical aspects of the disease, and reviews the current management approaches to this disorder. This article represents a starting point from which diagnostic and management decisions can undergo rigorous testing for efficacy. There is a lack of strong evidence and a requirement for further research. Nevertheless, providers need direction on how to recognize and care for BMMRD patients today. In addition to identifying areas of research, this article provides guidance for surveillance and management. The major challenge is that BMMRD is rare, limiting the ability to accumulate unbiased data and develop controlled prospective trials. The formation of effective international consortia that collaborate and share data is proposed to accelerate our understanding of this disease.
Background
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder most often caused by mutation in the
endoglin
or
ALK1
genes. A distinct syndrome combines the clinical ...features of HHT and juvenile polyposis (JP) and has been associated with
SMAD4
mutation. The aim of this study was to describe the phenotype of patients with JP–HHT and
SMAD4
mutations and to compare this phenotype with HHT or JP patients with mutations other than
SMAD4
.
Methods
Patients prospectively enrolled in the Toronto HHT and JP databases who underwent genotyping were included. The phenotypic characteristics of JP–HHT patients with
SMAD4
mutations and patients with mutations other than
SMAD4
were analyzed and compared.
Results
Three hundred and fifty-eight patients underwent genetic testing (HHT,
n
= 332; JP,
n
= 26). Among fourteen patients identified with
SMAD4
mutations, ten met the clinical diagnostic criteria for both JP and HHT (71%). Patients with
SMAD4
mutations had 100% penetrance of the polyposis phenotype. All patients with JP and
SMAD4
mutation had features of HHT. Three JP–HHT patients developed early onset colorectal cancer (CRC) (mean age 28 years). JP–HHT patients with
SMAD4
mutation had a significantly higher rate of anemia than HHT patients with mutations other than
SMAD4
.
Conclusions
Patients with HHT and
SMAD4
mutations are at significant risk of JP and CRC. The gastrointestinal phenotype is similar to JP patients without
SMAD4
mutation. It is essential for HHT patients to undergo genetic testing to determine if they have
SMAD4
mutations so that appropriate gastrointestinal screening and surveillance for JP and CRC can be completed.
Lynch syndrome: a pediatric perspective Huang, Sherry C; Durno, Carol A; Erdman, Steven H
Journal of pediatric gastroenterology and nutrition
58, Številka:
2
Journal Article
Recenzirano
Colorectal cancer is a rare disease in the pediatric age group and, when present, suggests an underlying genetic predisposition. The most common hereditary colon cancer susceptibility condition, ...Lynch syndrome (LS), previously known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant condition caused by a germline mutation in 1 of 4 DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, or PMS2. The mutation-prone phenotype of this disorder is associated with gastrointestinal, endometrial, and other cancers and is now being identified in both symptomatic adolescents with malignancy as well in asymptomatic mutation carriers who are at risk for a spectrum of gastrointestinal and other cancers later in life. We review the DNA MMR system, our present understanding of LS in the pediatric population, and discuss the newly identified biallelic form of the disease known as constitutional mismatch repair deficiency syndrome. Both family history and tumor characteristics can help to identify patients who should undergo genetic testing for these cancer predisposition syndromes. Patients who carry either single allele (LS) or double allele (constitutional mismatch repair deficiency syndrome) mutations in the MMR genes benefit from cancer surveillance programs that target both the digestive and extraintestinal cancer risk of these diseases. Because spontaneous mutation in any one of the MMR genes is extremely rare, genetic counseling and testing are suggested for all at-risk family members.
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