Multinodular goitre is a gateway for molecular testing of DICER1 syndrome

Abstract

Background DICER1 syndrome is an autosomal dominant disorder that predisposes individuals to develop benign or malignant tumours from infancy to adulthood. There is low‐to‐moderate penetrance of tumour development, which is sex‐ and age‐dependent. Multinodular goitre (MNG) is among the most highly penetrant phenotype of the disorder, especially in females. Patients and Methods We report a series of eight families referred for childhood‐onset of MNG or DICER1‐related tumours with familial history of MNG in relatives. No additional families with these criteria stated were identified during the same date. We screened DNA samples from the probands and members of their family (40) for constitutional DICER1 variants using Next Generation Sequencing tools. Results Germline pathogenic DICER1 gene variants were identified in all probands and several of their relatives: 64% presented with MNG/thyroidectomy as the phenotypic expression of the syndrome. DICER1 gene variants were identified in the RNAseIII and the PAZ domains. All tumour tissues studied presented clonal pathogenic variants in hotspot regions. Early identification of DICER1 variant carriers has permitted diagnosis and therapeutic scheme correction for two patients and cascade testing in relatives. Conclusions Multinodular goitre is uncommon in children. Childhood‐onset MNG, multiple occurrences of the disease within the same family, or its association with rare benign or malignant tumours should raise suspicions of anomalies in the DICER1 gene, as proposed by recent international recommendations. Early detection of DICER1 pathogenic variants has important consequences in terms of therapeutic strategy, early tumour screening, and genetic counselling.

Emerging Biomarkers in Thyroid Practice and Research

“…It has been proposed that germline DICER1 mutations are predisposed to thyroid follicular cell hyperplasia and the subsequent acquisition of one or more somatic RNase IIIb mutations results in the development of multiple thyroid nodules and MNG [ 40 ]. DICER1 syndrome should be suspected if MNG occurs in childhood, in a patient with an ovarian Sertoli –Leydig cell tumor or when familial [ 41 , 42 ].…”

Gene of the month:DICER1:ruler and controller

“…28 Multinodular goitre is frequently see in individuals with DICER1 syndrome being diagnosed in 30% of females and 13% of males by the age of 20 years. 38 DICER1 mutation also predisposes to a variety of thyroid tumours with follicular adenomas, follicular carcinomas, papillary carcinomas being reported. Somatic DICER1 mutations have also been associated with thyroid carcinosarcomas and teratomas.…”

Sertoli-Leydig cell tumor, thyroid follicular carcinoma and rhabdomyosarcoma of the uterine cervix in a prepubertal girl with pathogenic germline variant in DICER1 gene

“…13 Additionally, DICER1 sequencing has been recommended in children with multinodular goiter, multiple multinodular goiter cases within the same family, or its association with benign or malignant tumors. 14 Once a pathogenic variant is diagnosed in DICER1, follow up process of the patients is quite stressful for the clinician and the family members. The family members should be informed about the syndrome as well as the signs and symptoms of possible pathologies, and the clinician should be alert during surveillance and follow up.…”