A tale of two syndromes: An instructive case of two synchronous variants in ABCC8 and DICER1

Abstract

Aim: To determine the genetic aetiology for an ovarian tumour and a multinodular goitre (MNG) in an adolescent with a past history of congenital hyperinsulinism (CH). Patient details: The proband presented at 11 years with a sertolileydig cell tumour (SLCT). At 13 years, thyroidectomy was undertaken due to painful, tender and enlarging nodules of a MNG. She developed CH shortly after birth, requiring diaxozide until 24 months. She had infantile eczema and failure to thrive. A small bowel biopsy at 6 months showed partial-subtotal villous atrophy. A low allergen diet was commenced and gastrointestinal symptoms resolved by 22 months. Repeat biopsy had minimal inflammatory features. Developmental delay was noted during childhood. Her parents were not related. They reported maternal secondary degree relatives with papillary thyroid (n = 1), breast (n = 1) and ovarian cancer (n = 2); and cervical cancer in a paternal second degree relative. Genetic studies: Sequence analysis of genomic DNA for ABCC8 and KCNJ11 genes, identified an ABCC8 heterozygous missense mutation p.G316R (identified previously in patients with CH). Genetic analysis of parental DNA is pending. Sequence analysis of genomic DNA identified a germline DICER1 mutation c.5441C>T. Somatic DICER1 mutations c.5125G>A (p.D1709N) and c. 5425G>T were found in the SLCT and MNG respectively. Functional studies suggest these somatic mutants abrogate 5p miRNA generation. Conclusion: The ABCC8 and DICER1 variants are likely pathogenic accounting respectively for the CH and multiple endocrine neoplasia phenotype in this case. The aetiology of the autoimmune phenotype and developmental delay is not yet clear. The finding of genomic and somatic DICER1 variants in affected tissue is helpful toward accurate histopathological diagnoses of ovarian and thyroid conditions. Functional studies suggest that a critical amount of 5p miRNAs during organogenesis of susceptible tissues may be required for normal development.L720734522015-11-20 <br />