Scholarly article on topic 'A novel DICER1 mutation identified in a female with ovarian Sertoli-Leydig cell tumor and multinodular goiter: a case report'

A novel DICER1 mutation identified in a female with ovarian Sertoli-Leydig cell tumor and multinodular goiter: a case report Academic research paper on "Clinical medicine"

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Academic research paper on topic "A novel DICER1 mutation identified in a female with ovarian Sertoli-Leydig cell tumor and multinodular goiter: a case report"

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Y ~ CASE REPORTS

CASE REPORT Open Access

A novel DICER1 mutation identified in a female with ovarian Sertoli-Leydig cell tumor and multinodular goiter: a case report

Maria Rossing1, Anne-Marie Gerdes2, Anders Juul3, Catherine Rechnitzer4, Martin Rudnicki5, Finn C Nielsen1 and Thomas vO Hansen1*

Abstract

Introduction: Germ-line mutations in the micro-ribonucleic acid processing gene DICER! have been shown to predispose to a subset of benign tumors susceptible to malignant transformation, including ovarian Sertoli-Leydig cell tumor, nontoxic multinodular goiter, multilocular cystic nephroma and pleuropulmonary blastoma, which can occur in children and young adults. This may be due to reduced Dcr-1 homolog expression in carriers of germline mutations, which causes impairment of micro-ribonucleic acid processing and deregulates the growth and differentiation of target cells, leading to an increased risk of tumorigenesis. Many carriers of germ-line DICER! mutations remain unaffected, but development of tumors within carriers is associated with varying prognoses.

Case presentation: Despite the Dcr-1 homolog syndrome phenotype being incompletely defined, a DICER! mutation was suspected when a girl (case 1 patient) of Danish ethnicity presented with both an ovarian Sertoli-Leydig cell tumor and a multinodular goiter at the age of 13 years. In addition, family history included a male sibling (case 2 patient) who also had a multinodular goiter and had undergone a hemithyroidectomy at the age of 14 years. Subsequent DICER! screening of the girl identified two novel mutations in exon 21 - a nonsense (c.3647C>A, p.Ser1216*) and a missense (c.3649T>A, p.Tyr1217Asn) mutation. The siblings had inherited the mutations from their father and paternal grandfather, which both currently were asymptomatic, indicating reduced penetrance of the nonsense mutation. Analysis of the parents revealed that the mutations were present in cis, making the contribution of the missense mutation less significant.

Conclusion: We report a novel pathogenic DICER! mutation (p.Ser1216*) in a Danish family associated with ovarian Sertoli-Leydig cell tumor and a multinodular goiter. A multinodular goiter was diagnosed in the siblings during childhood. Clinicians should be aware of a potential germ-line DICER! mutation when evaluating multinodular goiter in young patients with or without a family history of thyroid diseases.

Keywords: DICER!, Germ-line mutation, Multinodular goiter, Ovarian Sertoli-Leydig cell tumor

Introduction

Dcr-1 homolog (DICER1) is a member of the ribonucle-ase type III family and plays an important role in the processing and maturation of micro-ribonucleic acids (miRNAs) [1]. miRNAs are small (20 to 25 nucleotides), double-stranded, non-coding, endogenous RNA molecules that modulate gene expression at the post-transcriptional

* Correspondence: Thomas.Van.Overeem.Hansen@regionh.dk 1Centerfor Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

Full list of author information is available at the end of the article

Bio Med Central

level by imperfect base pairing to the complementary sequences on target messenger RNAs (mRNAs). miRNA genes are transcribed by RNA polymerase II or III into primary miRNA transcripts termed pri-miRNAs. Pri-miRNAs are subsequently cleaved by the Drosha-DGCR8 complex to release hairpin-shaped pre-miRNAs. Pre-miRNAs are exported to the cytoplasm where DICER1 cuts their terminal loop and generates short miRNA duplexes. A single strand of the small RNA duplexes is finally incorporated into the RNA-induced silencing complex, and in this

© 2014 Rossing et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, anc reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

position, miRNAs bind to their target mRNAs, modulating protein expression [1].

Impaired DICER1 expression and subsequent altered miRNA processing have a substantial impact on the dys-regulation of target oncogenes, leading to enhanced tumorigenesis [2]. DICER1 mutations have previously been associated with ovarian Sertoli-Leydig cell tumor (SLCT), nontoxic multinodular goiter (MNG) and multi-locular cystic nephroma. These conditions generally follow a benign course [3,4]. In addition, DICER1 mutations predispose to a rare type of lung cancer most often seen in children, known as pleuropulmonary blastoma [5]. Recently, DICER1 mutations were also suggested to be associated with diseases, such as Wilms' tumor, cervix embryonal rhabdomyosarcoma and pineoblastoma [6-8].

Here we report a novel germ-line DICER1 nonsense mutation in a pair of siblings with MNG, as well as SLCT in the index case.

Case presentation

Case 1 patient was a 13-year-old girl of Danish ethnicity (proband), who presented with swelling of the neck, as well as a deep voice, hirsutism and acne vulgaris in the beard area of the face. She was subsequently diagnosed with MNG and ultrasonic examination identified 13

nodules ranging from 6 to 12mm in size. Examination of her hormonal status revealed increased levels of andro-stenedione (26nmol/l) and testosterone (total: 6.8nmol/l and free: 0.146nmol/l). Follicle-stimulating hormone and luteinizing hormone levels were normal, as was the Synacthen test. A computed tomography scan identified a tumor in her left ovary. She immediately underwent unilateral oophorectomy and subsequent histopathological examination detected encapsulated tumor tissue, including strings of immature and slightly atypical Sertoli cells together with accumulations of Leydig cells. There were only a few mitoses and no necrosis. The final histopatho-logical diagnosis was reported as an encapsulated SLCT of intermediate degree of differentiation. Immunohistochem-ical analyses showed positive staining for vimentin and inhibin, whereas a-fetoprotein gave a negative result. Follow-up included an ultrasonic-guided examination of the ovary and measurement of hormonal status and serum inhibin B level for five years with an increasing interval.

c a a c tac ct 4 33

GATAT 439

c c a t t c 445

ca actacctNaNatt ccat tc 433 439 445 4

c.3647C>A c.3649T>A p.Ser1216X p.Tyr1217Asn

Figure 1 Identification of the DICER1 c.3647C>A, p.Ser1216* and the c.3649T>A, p.Tyr1217Asn mutations. Deoxyribonucleic acid was purified from blood samples from a wild-type and the proband. The DICER1 gene was amplified using intronic primer pairs flanking each exon, followed by sequencing. The analysis revealed a DICER1 nucleotide c.3647C>A, pSer1216* mutation in exon 21 and a DICER1 nucleotide c.3649T>A, p.Tyr1217Asn mutation also in exon 21 in the proband (panelB) not present in the wild-type (panel A).

MNG 14 MNG 13

Ovarian SLCT 13

Figure 2 Family pedigree. Multinodular goiter and ovariar Sertoli-Leydig celltumor are indicated as well as the age at diagnosis. Diagonal slash indicates deceased, while the proband is indicated with an arrow. Mutation-positive individuals are indicated with +. MNG, multinodular goiter; SLCT, Sertoli-Leydig cell tumor.

Table 1 Previously reported germ-line mutations in the DICER1 gene

Region

Nucleotide change

Amino acid change Reference

Exon 4 c.328_338dupGTGTCAGCTGT

Exon 7 c.876_879delAAAG

Exon 8 c.912_919dupAGACTGTC

Exon 8 c.1128_1132delAGTAA

Exon 8 c.1153delC

Exon 8 c.1196_1197dupAG

Exon 8 c.1306dupT

Exon 9 c.1507G>T

Exon 10 c.1525C>T

Exon 10 c.1684_1685delAT

Exon 10 c.1716delT

Exon 12 c.1910dupA

Exon 12 c.1966C>T

Intron 12 c.2040+1G>C

Intron 13 c.2117-1G>A

Exon 14 c.2245_2248dupTACC

Exon 14 c.2247C>A

Exon 15 c.2268_2271delTTTG

Exon 15 c.2392dupA

Exon 16 c.2457C>G

r.2437_2457del21

Exon 16 c.2516C>T

Intron 17 c.2805-1G>T

r.2805_2987del183

Exon 18 c.2830C>T

Intron 18 c.2988-2_2988-1delAGinsCT

Exon 21 c.3270-6_4051 - 1280delinsG

Exon 21 c.3288_3289insTTTC

Exon 21 c.3505delT

Exon 21 c.3540C>A

Exon 21 c.3583_3584delGA

Exon 21 c.3611_3616delACTACAinsT

Exon 21 c.3647C>A

Exon 21 c.3665delT

Exon 21 c.3726C>A

Exon 21 c.3793delA

Exon 21 c.3907_3908delCT

Intron 21 c.4050+1delG

Exon 23 c.4309_4312delGACT

Exon 23 c.4403_4406delCTCT

Exon 23 c.4740G>T

Exon 23 c.4748T>G

Exon 23 c.5018_5021delTCAA

Exon 24 c.5104C>T

p.Arg114Cysfs*18

p.Arg293Ilefs*4

p.Arg307Glnfs*8

p.Lys376Asnfs*11

p.Arg385Alafs*73

p.Trp400Serfs*59

p.Ser436Phefs*41

p.Glu503*

p.Arg509*

p.Met562Valfs*11

p.Phe572Leufs*15

p.Tyr637*

p.Arg656*

p.Pro750Leufs*12

p.Tyr749*

p.Cys756*

p.Thr798Asnfs*33

p.Ile813_Tyr819del

p.Ser839Phe p.Tyr936

p.Arg944* p.?

p.Tyr1091Ser*28

p.Gly1097Phefs*8

p.Ser1169Glnfs*23

p.Tyr1180*

p.Asp1195Leufs*39

p.Tyr1204Leufs*29

p.Ser1216*

p.Leu1222Tyrfs*17

p.Tyr1242*

p.Thr1265Glnfs*37

p.Leu1303Valfs*4

p.Asp1437Metfs*16

p.Ser1468Phefs*21

p.Gln1580His

p.Leu1583Arg

p.Ile1673Thrfs*31

p.Gln1702*

Slade etal. [11]

Rio Frio et al. [4]

Foulkes et al. [7]

Sabbaghian et al. [8]

Slade etal. [11]

Slade etal. [11]

Foulkes et al. [7]

Hill etal. [5]

Darrat etal. 2013

Hill et al. [5]

Slade etal. [11]

Doros etal. [10]; Hill etal. [5]

Foulkes etal. [7]; Slade etal. [1'

Slade etal. [11]

Foulkes et al. [7]

Hill et al. [5]

Doros etal. [10]; Hill etal. [5] Slade etal. [11] Hill et al. [5] Rio Frio et al. [4]

Rio Frio et al. [4] Rio Frio et al. [4]

Hill et al. [5] Slade etal. [11] Sabbaghian et al. [13] Slade etal. [11] Slade etal. [11] Hill et al. [5] Slade etal. [11] Foulkes et al. [7] This study Slade etal. [11] Slade etal. [11] Slade etal. [11] Foulkes et al. [7] Foulkes et al. [7]

Bahubeshi etal. [3]; Doros etal. [10]

Slade etal. [11]

Slade etal. [11]

Hill et al. [5]

Rio Frio et al. [4]

Doros et al. [10]; Dehner et al. [9]

: Hill et al. [5] (reported in four individuals)

Table 1 Previously reported germ-line mutations in the DICER1 gene (Continued)

Exon 24 c.5122_5128delGGAGATG p.Gly1708Argfs*7 Slade eta!. [11]

Exon 25 c.5465A>T p.Asp1822ValSlade et a!. [11]

Exon 25 c.5477C>A p.Ser1826* Bahubeshi et a!. [3]

Some of the information is obtained from [https://grenada.lumc.nl/LOVD2/mendelian_genes/home.php?select_db=DICER1]. NM177438.2 was used as a reference sequence.

Since our proband, had an ovarian SLCT as well as MNG, the pediatricians suspected a DICER1 mutation and referred the girl for genetic counseling. Blood samples were collected, genomic deoxyribonucleic acid (DNA) was purified, and the entire coding region and the exon-intron boundaries of DICER1 were screened. The analysis identified two mutations in exon 21 - a nonsense mutation (c.3647C>A, p.Ser1216*) and a missense mutation (c.3649T>A, p.Tyr1217-Asn) of unknown significance (Figure 1, panel B).

Since a pathogenic DICER1 mutation was identified, first and second degree relatives of the proband were screened for the mutation. The analyses revealed that the brother, the father and the paternal grandfather all carried the pathogenic DICER1 mutation as well as the missense mutation (Figure 2), indicating that the two mutations are present in cis on the same allele.

Case 2 patient is a five-year older brother of the proband who had an MNG and underwent hemithyroidectomy at the age of 14. Ultrasound (US)-guided fine-needle aspirate from the dominating hypoechoic cold nodule measuring (4x3.5x2.5cm) yielded follicular neoplasia. Subsequently, the brother underwent a right-sided hemi-thyroidectomy and the histopathological examination revealed an encapsulated follicular adenoma with papillary hyperplasia. The brother is at present time in his early 20s and remains eu-thyroid without any pressure symptoms. He has annual consultations regarding the MNG of the left lobe to monitor potential growth in the cold nodules.

The father, at the age of 50, has no chronic illnesses and no medical history of any thyroid symptoms. A recent thyroid check-up confirmed the euthyroid status and a normal palpatory examination of the thyroid and neck area. The medical history of the paternal grandfather reveals a remarkably fit patient in his mid-80s who is being treated for hypertension and hypercholes-terolemia. The grandfather remains euthyroid and palpa-toric examination of the thyroid and neck area did not reveal any goiter, nodules or enlarged lymph nodes.

Discussion

Ovarian SLCTs are rare androgen-producing sex cord-gonadal stromal tumors that account for less than 1% of ovarian tumors, occurring most commonly in younger women while MNG is a common disease likely caused by low iodine intake but also with a heritable predisposition. In this study, a girl was diagnosed with MNG and

ovarian SLCT at the age of 13 years. Subsequently, a pathogenic DICER1 mutation was identified. To date, 45 different pathogenic germ-line DICER1 mutations have been reported in 53 probands with various neoplasms worldwide, including frameshift, nonsense, splicing and missense mutations scattered throughout the gene, as well as large genomic rearrangements (Table 1) [3-5,7-13]. The novel nonsense mutation identified in the present study resides in exon 21, the largest exon of DICER1, where currently 11 other pathogenic germ-line mutations and deletions have been identified. Hence, exon 21 of the DICER1 gene has the highest frequency of disease-causing mutations, followed by exons 8 and 23 with five pathogenic mutations each. Exon 21 is of particular interest as it encodes a large part of the ribonuclease (RNase) IIIa domain. The RNase IIIa domain is highly important for the production of miRNAs from the 3' arm of precursors and forms, together with RNase IIIb, the core catalytic element of Dicer1.

Our data indicate reduced penetrance of the c.3647C>A DICER1 mutation. At the time of our study, two of the adult family members showed no signs of neoplasms, whereas the mutation was associated with characteristic tumors at an early age in the proband and her brother. The relatively low penetrance in the described family is in line with other reported familial DICER1 mutations [3,4,14]. The low penetrance of DICER1 mutations could relate to a decisive role of miRNAs in the differentiation of stem cells [15], assuming a significant intrauterine selection pressure against the mutations in combination with variations in genetic background. Although the level of penetrance of DICER1 mutations seems modest, mutational screening of DICER1 in children and young persons with MNG as well as rare tumors of the ovary, eyes, lungs or kidneys could still be useful. Such screening might also be important in cases devoid of a family history. However, the apparent modest level of penetrance makes the issue of intrauterine testing for the mutation ethically debatable. Genetic counseling of parents of children with a recognized DICER1 mutation who intend to have more children would benefit from a more precise knowledge of the tumorigenic pene-trance of the different DICER1 mutations. Therefore, clinical follow-up studies of patients with pathogenic DICER1 mutations with and without neoplastic diseases are required for improved counseling and treatment.

Conclusions

Very few clinicians couple the rare SLCT with the more common MNG and it is therefore reasonable to assume that the syndromes associated with DICER1 mutations are under diagnosed. Based on the findings in the present case report, future awareness of SLCT and MNG should reveal a more accurate incidence. Moreover, clinicians should be aware of a potential germ-line DICER1 mutation when evaluating multinodular goiter in young patients with or without a family history of thyroid diseases.

Consent

Written informed consent was obtained from the first patient's (Case 1) legal guardian and all other involved patients for publication of this case report and accompanying images. Copies of the written consents are available for review by the Editor-in-Chief of this journal.

Abbreviations

mRNAs: Messenger RNAs; miRNAs: microRNAs; MNG: Multinodular goiter; SLCT: Sertoli-Leydig celltumor; US: Ultrasound.

Competing interests

The authors declare that they have no competing interests. Authors' contributions

MR, TvOH and FCN were involved in the genetic screening of the patients. AJ, CR, MRu and AMG performed the clinicalexaminations and the genetic counseling of the patients. MR and TvOH drafted the manuscript, while FCN, AJ, CR, MRu and AMG were involved in the revision of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

We thank Stine 0stergaard and Shehrukh Jamilfor technicalassistance. We also thank the patients reported in this case report for their consent to publish the findings.

Author details

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 2Department of ClinicalGenetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 3Department of Growth and Reproduction, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 4Department of Pediatrics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 5Department of Obstetrics and Gynecology, Roskilde University Hospital, Roskilde, Denmark.

Received: 10 September 2013 Accepted: 13 January 2014 Published: 3 April 2014

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doi:10.1186/1752-1947-8-112

Cite this article as: Rossing et al.: A novel DICER1 mutation identified in a female with ovarian Sertoli-Leydig cell tumor and multinodular goiter: a case report. Journal of Medical Case Reports 2014 8:112.

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