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

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes, poorly recognised by clinicians so far. METHODS: Retrospective review of all 31 patients with CMMRD diagnosed in French genetics laboratories in order to describe the characteristics, treatment and outcome of the malignancies and biological diagnostic data. RESULTS: 67 tumours were diagnosed in 31 patients, 25 (37%) Lynch syndrome-associated malignancies, 22 (33%) brain tumours, 17 (25%) haematological malignancies and 3 (5%) sarcomas. The median age of onset of the first tumour was 6.9 years (1.2-33.5). Overall, 22 patients died, 9 (41%) due to the primary tumour. Median survival after the diagnosis of the primary tumour was 27 months (0.26-213.2). Failure rate seemed to be higher than expected especially for T-cell non-Hodgkin's lymphoma (progression/relapse in 6/12 patients). A familial history of Lynch syndrome was identified in 6/23 families, and consanguinity in 9/23 families. PMS2 mutations (n=18) were more frequent than other mutations (MSH6 (n=6), MLH1 (n=4) and MSH2 (n=3)). CONCLUSIONS: In conclusion, this unselected series of patients confirms the extreme severity of this syndrome with a high mortality rate mostly related to multiple childhood cancers, and highlights the need for its early detection in order to adapt treatment and surveillance.

Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium "Care for CMMR-D" (C4CMMR-D).

Lynch syndrome (LS) is an autosomal dominant disorder caused by a defect in one of the DNA mismatch repair genes: MLH1, MSH2, MSH6 and PMS2. In the last 15 years, an increasing number of patients have been described with biallelic mismatch repair gene mutations causing a syndrome referred to as 'constitutional mismatch repair-deficiency' (CMMR-D). The spectrum of cancers observed in this syndrome differs from that found in LS, as about half develop brain tumours, around half develop digestive tract cancers and a third develop haematological malignancies. Brain tumours and haematological malignancies are mainly diagnosed in the first decade of life, and colorectal cancer (CRC) and small bowel cancer in the second and third decades of life. Surveillance for CRC in patients with LS is very effective. Therefore, an important question is whether surveillance for the most common CMMR-D-associated cancers will also be effective. Recently, a new European consortium was established with the aim of improving care for patients with CMMR-D. At a workshop of this group held in Paris in June 2013, one of the issues addressed was the development of surveillance guidelines. In 1968, criteria were proposed by WHO that should be met prior to the implementation of screening programmes. These criteria were used to assess surveillance in CMMR-D. The evaluation showed that surveillance for CRC is the only part of the programme that largely complies with the WHO criteria. The values of all other suggested screening protocols are unknown. In particular, it is questionable whether surveillance for haematological malignancies improves the already favourable outcome for patients with these tumours. Based on the available knowledge and the discussions at the workshop, the European consortium proposed a surveillance protocol. Prospective collection of all results of the surveillance is needed to evaluate the effectiveness of the programme.

Nonathymulin treatment of multiple sclerosis: double-blind pilot study.

We carried out a randomized, double-blind, placebo-controlled trial of Nonathymulin (NT, synthetic serum thymic factor) in patients with evolutive multiple sclerosis (MS) and moderate disability. Forty matched patients were treated with subcutaneous NT or placebo for 6 months and followed for another 6 months. There was no significant difference in treatment and control groups in the Kurtzke. Disability scores, Ambulation Index and Functional Scale. No significant side effects were recorded. NT is not effective in treating evolutive and moderately disabled MS.

Scanning and transmission electron microscopy study of ferret respiratory mucosa infected with influenza A virus.

The use of both SEM and TEM techniques in studying the alterations of the columnar ciliated epithelium of the whole respiratory tract of ferrets enables the authors to find a significant discrepancy between tracheal and nasal mucosa destructions. This discrepancy is not a function of the anatomical location of virus instillation. Theoretical and pratical meanings are discussed.

Prophylactic and therapeutic effects of murabutide in OF1 mice infected with influenza A/H3N2 (A/Texas/1/77) virus.

The antiviral activity of a novel biological response modifier (murabutide MDP derivative) has been investigated in 3-week-old OF1 mice infected with influenza (A/Texas/1/77) virus. In each experimental and control group, 10 mice were infected intranasally with a viral dose producing 50% mortality in 5 days and received murabutide via the subcutaneous or intranasal route at various doses either in a simple or in daily repeated administration. All experiments were done in triplicate. Significant prophylactic or therapeutic effects were observed when murabutide was administered the same day as virus, 4 days or 2 days before virus, and 2 days later. These effects varied with the route of administration and the doses of the compound.