Review
Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome

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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.

Introduction

Lynch syndrome is the most common inherited colorectal cancer syndrome in adults. It is an autosomal dominant condition caused by heterozygous germ-line mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. However, inheriting biallelic (homozygous) mutations in any of the MMR genes results in a different clinical syndrome termed biallelic mismatch repair deficiency (BMMR-D). The more severe BMMR-D phenotype presents with cancer during childhood and is characterised by gastrointestinal tumours, brain tumours and haematologic malignancies [1]. Colorectal and small bowel adenomatous polyps are a phenotypic feature of BMMR-D. Children surviving the initial malignancy and adults presenting with BMMR-D can develop gastrointestinal malignancies most commonly, colorectal and small bowel cancers, which is the presenting tumour in up to two-thirds of patients with BMMR-D [2]. Individuals with BMMR-D have café-au-lait (CAL) macules and other features more typically associated with neurofibromatosis type 1 (NF-1).

BMMR-D is an under-recognised clinical syndrome that can present with advanced disease. In contrast to juvenile inflammatory polyps, which commonly present with painless rectal bleeding, adenomatous polyps are often asymptomatic [7]. Furthermore, the progression from adenoma to carcinoma can be rapid in BMMR-D. Consequently, patients with BMMR-D can present with intestinal cancer and metastatic disease before the onset of any relevant intestinal or systemic symptoms [8].

Many patients labelled as having Turcot syndrome were noted to have café-au-lait macules and then were reclassified as BMMR-D because they carry biallelic mutations in MMR genes [4]. Turcot syndrome was characterised by the joint occurrence of a brain tumour and multiple colorectal adenomas. Turcot syndrome was originally considered to be a phenotypic variant of either familial adenomatous polyposis (FAP) or Lynch syndrome, with medulloblastomas associated with the former and glioblastomas associated with the latter [3]. Other patients with multiple colonic adenomatous polyps, some with café-au-lait macules, but in the absence of brain tumours, were previously characterised as having FAP or attenuated FAP even though no APC gene mutation is identified [5], [6]. It is now evident that all such patients should undergo genetic evaluation for the possible underlying diagnosis of BMMR-D.

In order to better define the clinical and genetic characteristics of BMMR-D, an international consortium has been formed to collect clinical data, obtain tumour tissue and provide genetic testing to increase current understanding of BMMR-D and, ultimately, improve patient outcomes. Specialists in internal medicine, paediatrics, clinical genetics, dermatology, gastroenterology and haematology/oncology are each in a position to recognise probable BMMR-D patients so that appropriate surveillance can be offered and families referred for genetic counselling.

Here we review data from published case series and the BMMR-D consortium over the last decade. Special emphasis is given to important clues for the treating physician who manages such individuals and families.

Section snippets

Clinical presentations

Café-au-lait skin macules are the most common feature reported in the majority of BMMR-D patients [1]. Health care providers should recognise characteristic features of café-au-lait macules observed in BMMR-D; within the hyper-pigmented macules there are frequently areas of hypopigmentation and the borders of the skin lesions in BMMR-D are more diffuse and irregular than in classic CAL (Fig. 1). Number of skin lesions is variable, ranging from only one or two focal areas to more diffuse areas

Family history

An important clue in the family history that suggest underling BMMR-D is parental consanguinity, which is present in more than half of BMMR-D families [1], [2]. BMMR-D is more common in families originating from south Asia where consanguinity is common. Pedigrees of BMMR-D patients typically show a paucity of Lynch syndrome cancers and most parents are unaffected. Out of 20 families followed by the consortium, none of the parents had a history of or developed a Lynch related tumour during

Characterisation of the gastrointestinal phenotype

The phenotypic spectrum of BMMR-D is wide [2]. Adenomatous polyps have been identified in both the small intestine and large bowel of BMMR-D patients. The number of polyps is extremely variable ranging from less than five to 50. Gastric polyps have been described [2], [9]. Both duodenal and jejunal carcinomas also can occur [6], [8], [10]. These observations highlight the need for comprehensive GI tract surveillance, including both upper and lower endoscopies, and possibly capsule endoscopy, in

Brain tumours

Brain tumours are common cancers in BMMR-D [1] especially during the first two decades. Data gathered from the consortium suggest that malignant brain cancers are the most common presentation of the syndrome during childhood [12]. Some authors suggest that there is an association of brain tumours with PMS2/MSH6 mutations [1]. The spectrum of brain cancers in BMMR-D are most commonly high-grade gliomas followed by primitive neuroectodermal tumour and medulloblastoma. A central pathology review

Haematological malignancies

All major types of leukaemias and lymphomas have been reported in BMMR-D; however, there is a high prevalence of lymphoid malignancies, most commonly T-cell lymphomas [1]. This may be relevant since patients with BMMR-D have immunoglobulin inefficient class-switch changes and can have sub-clinical immune deficiency [13]. Although less common, myeloid leukaemias are also reported in BMMR-D. Chronic myelomonocytic leukaemia, which is observed in children with NF-1, has not been reported in BMMR-D

Extra-intestinal Lynch-associated tumours

Eight patients with uterine cancer have been reported in BMMR-D. These patients ranged in age between 23 and 35 years [1], [14], [15], [16]. To date, three patients (10–21 years of age) have been diagnosed with ureteric, renal pelvis, and bladder cancer respectively [6], [10]. A number of these patients presented with a first malignancy in adulthood, consistent with a milder BMMR-D phenotype. Clinicians caring for patients with uterine and specific urologic malignancies must closely evaluate

Emerging phenotypes

As BMMR-D becomes better recognised and more patients are genotyped, systematic data collection will allow for a more comprehensive understanding of the cancer spectrum, as well as genotype:phenotype relationships. Surveillance of the brain with magnetic resonance imaging reveal other central nervous system anomalies such as agenesis of the corpus callosum, the first congenital abnormality associated with BMMR-D and vascular anomalies [17], [18]. Data gathered from the consortium and other case

Diagnostic evaluation

Tumours with MMR deficiency demonstrate a high frequency of somatic microsatellite instability (MSI). MSI is the hallmark of MMR-deficient colon cancer and serves as a screening tool for diagnosing Lynch syndrome [21]. In contrast to Lynch syndrome, the role of tumour microsatellite instability (MSI) in screening for BMMR-D remains controversial [22], [23]. Data gathered from the consortium on more than 31 tumours reveal stable microsatellite in the vast majority of brain tumours and

Functional tests in challenging cases

In some kindred it can be difficult to identify the specific gene mutation despite evidence of a convincing BMMR-D phenotype and an absence of tumour protein staining. Skin biopsies can be evaluated in kindred in this setting. We studied skin biopsies from a kindred of six individuals with a proband suspected of having BMMR-D with possible PMS2 mutation based on negative tumour staining. IHC of these skin biopsies revealed positive staining in family members and no staining in skin biopsies

Tumour surveillance

Evidence-based gastrointestinal screening and surveillance recommendations in Lynch syndrome were developed based on prospective trials involving large series of patients. By contrast, there is limited experience and, therefore, no evidence-based screening guidelines for BMMR-D. There is also no literature evaluating long-term outcomes in patients with BMMR-D. Clinical surveillance strategies aimed at early detection of a diverse tumour spectrum has been successfully implemented for other

Genetic counselling

The genetic counsellor plays a key role in the management of families with BMMR-D. As in any clinical encounter, counsellors must be sensitive to the diverse cultural and religious beliefs held by families. There may be a cultural acceptance of consanguineous marriage and discussions of inheritance as a result of such a relationship must be handled with great care and considerable sensitivity. For cultural or religious reasons, some families may not be comfortable with genetic testing. Despite

Summary

BMMR-D is a newly recognised syndrome for which both phenotypic and genotypic data are still emerging. The presence of café-au-lait macules and other signs of NF-1 in a patient with BMMR-D related tumours, particularly in consanguineous kindred, must raise the suspicion of a possible underlying diagnosis of BMMR-D. Molecular and genetic tests aid in screening and diagnosis of this rare, yet clinically and genetically informative, syndrome. Detection of BMMR-D can lead to more appropriate

Funding

The Zane Cohen Center for Digestive Diseases. BRAINchild Canada and Canadian Institute of Health Research.

Conflict of interest statement

None declared.

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