Germline and somatic mosaicism in a family with multiple endocrine neoplasia type 1 (MEN1) syndrome

in European Journal of Endocrinology
Correspondence should be addressed to M J E Kempers; Email:
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Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1 and can be diagnosed based on clinical, familial and/or genetic criteria. We present a family in which we found both germline and somatic mosaicism for MEN1.

Family description

In our proband, we diagnosed MEN1. The mutation was not detected in her parents (DNA extracted from leucocytes). When her brother was found to harbor the same MEN1 mutation as our proband and, around the same time, their father was diagnosed with a neuroendocrine carcinoma, this tumor was investigated for the MEN1 mutation as well. In the histologic biopsy of this tumor, the same MEN1 mutation was detected as previously found in his children. Re-analysis of his blood using multiplex ligation-dependent probe amplification (MLPA) showed a minimal, but consistently decreased signal for the MEN1-specific MLPA probes. The deletion was confirmed in his son by high-resolution array analysis. Based on the array data, we concluded that the deletion was limited to the MEN1 gene and that the father had both germline and somatic mosaicism for MEN1.


To our knowledge, this is the first reported family with combined germline and somatic mosaicism for MEN1. This study illustrates that germline mosaicism is important to consider in apparently sporadic de novo MEN1 mutations, because of its particular importance for genetic counseling, specifically when evaluating the risk for family members and when considering the possibility of somatic mosaicism in the parent with germline mosaicism.

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    Pedigree. Boxes indicate male subjects; circles indicate female subjects. Black boxes/circles indicate the presence of the MEN1 mutation. Oblique line indicates that the respective subject has deceased. The small black box in patient II:3 indicates the presence of germline and somatic mosaicism. Arrow points at index patient.

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    MLPA result. (A) MLPA results of the MEN1 deletion in DNA extracted from peripheral blood of the index (red circles) and his father (green squares and blue triangles correspond to two different blood drawings, purple diamonds to DNA from an oral mucosa swap). Each data point is an average of two analyses. Gene dosage was calculated by dividing the peak area of the probes by the combined area of the control probes. This was compared to the ratio of five control samples using MLPA kit P017-C1. (B) High-resolution array analysis (CytoscanHD (Thermo Fisher)) showing the deletion in the MEN1 gene. The deletion is limited to the MEN1 gene with the proximal breakpoint within MEN1 (in exon 8/intron 8) and the distal breakpoint in (5′ of intron 7) or upstream of MEN1 (based on NM_130799.2). The location of the deletion is indicated by the arrow.


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