Course:MEDG550/Student Activities/DICER-1 Syndrome
DICER-1 syndrome is a genetic disorder associated with an increased risk to developing specific types of tumors. The highest risk for DICER-1 associated tumors is in early childhood[1]. Most individuals who are affected by DICER-1 related features are diagnosed before the age of 40 years[1][2] . The types of tumors associated with DICER1 syndrome include both life-threatening cancers, and non-life threatening (benign) tumors.
Features of DICER-1 Syndrome
Individuals affected by DICER-1 syndrome have been reported to have an increased risk to developing both common and rare types of tumors in several different systems of the body. The most commonly affected systems are the lungs, thyroid gland, kidneys and ovaries[1][3][4]. Below is an incomplete list of features and tumors that have been associated with DICER-1 syndrome. For the more common features of DICER-1 syndrome, short descriptions and estimated risks have been included. For the more rare features associated with DICER-1, there are no reliable risk estimates available at this time.
N.B.: Individuals with DICER-1 syndrome have an increased risk for developing the following features but ~80% of all individuals with DICER-1 syndrome will never develop a life-threatening tumor or cancer[5].
Pleuropulmonary blastoma (PPB) and pulmonary cysts
Pleuropulmonary blastoma (PPB) is a type of childhood lung cancer tumor which mostly affects infants and young children under the age of 6 years old[2]. In the early stages of PPB, air-filled pouches, called cysts, form inside either one or both lungs of babies. These cysts can later grow into solid tumors that can spread throughout the body. In some cases, it is possible to detect PPB during the 3rd trimester of pregnancy[4]. If caught early enough, surgical removal of PPB can be curative. If not caught early enough, the disease can progress within the lungs and spread to other parts of the body. PPB can be deadly without medical intervention[6].
PPB is one of the most common features of DICER-1 syndrome, and is the most common life-threatening feature[2]. It is estimated that less than 10% of individuals with DICER-1 syndrome will develop PPB, whereas ~25-40% will develop non-life-threatening (benign) pulmonary cysts. PPB is very rare in the general population, and it is estimated that 65% of children diagnosed with PPB are affected by DICER-1 syndrome [2][6]. This type of lung tumor is not associated with adult lung cancers. DICER-1 carriers are also at an increased risk for developing common lung cysts.
Symptoms of PPB are similar to those of pneumonia (lung infection), and include:
- Difficulties breathing or shortness of breath
- Fever
- Weight loss
- Pneumothorax (collapsed lung)
Thyroid diseases
Multinodular goiter (MNG)
DICER-1 syndrome's most common feature[7]. Thyroid nodules and MNG are conditions in which one, or more commonly, both sides of the thyroid gland develops many benign lumps; either cysts or nodules. Cysts are air-filled sacs, whereas nodules are solid masses. The function of the thyroid gland is not typically affected by these lumps, however most affected individuals will not have any symptoms[1]. MNGs are typically diagnosed due to lumps felt in the throat by the individual or a physician. Although both thyroid nodules and MNG is common in the general population, individuals affected by DICER-1 are more likely to develop these disorders, and at younger ages. In individuals with DICER-1 syndrome, thyroid nodules tend to develop between the ages of 10-40 years old, however they can occur as young as 5 years old[4][7].
Thyroid diseases are more common in females affected by DICER-1. It is estimated that 75% of women affected by DICER-1 syndrome will develop benign thyroid nodules or MNG, whereas the risk for men affected by DICER-1 is about 17%[7].
Differentiated Thyroid Cancer
Although rare, individuals with DICER-1 syndrome do carry an increased risk for developing thyroid cancer. It has been estimated that individuals affected by DICER-1 have a 15-40% risk for developing differentiated thyroid cancers by the age of 40 years[7]. As with MNG, the risk is about 3x higher in women affected by DICER-1.
It is believed that the increased thyroid cancer risk associated with DICER-1 syndrome is due to the increased development of benign thyroid nodules and MNGs. Although these thyroid disorders typically remain benign, they appear to be more likely to become cancerous than normal thyroid glands[5][8].
Female gynecological tumors
Gynecological tumors associated with DICER-1 syndrome in women include sex-chord stromal tumors affecting the ovaries or the cervix[2]. Most DICER-1 associated gynecological tumors are diagnosed during the reproductive years. It is reported that 95% of individuals with DICER-1 syndrome-associated ovarian tumors were diagnosed before the age of 40 years (1), however the range of age at diagnosis ranges from 4 years to 62 years old[3]. It is estimated that less than 10% of women affected with DICER-1 syndrome are affected with Ovarian sex-chord stromal tumors or other tumor associated with the female reproductive tract[1][3][4].
Sertoli-Leydig cell tumor (SLCT)
SLCT is an ovarian cancer which is very rare in the general population. It is the most common type of ovarian cancer to develop in association with DICER-1 syndrome in women[5]. As with the other sex-chord stromal tumors listed below, women affected SLCT will often develop male sex characteristics in the early stages of the disease. This is due to the fact that the SLCT tumor cells will often produce the male hormone, testosterone. The symptoms includes:
- Growth of hair in male-patterns (eg. facial hair, chest hair, back hair, etc..)
- Deepening of the voice
- Stopping of menstrual periods
- decrease in breast size
- Enlarged clitoris
Other tumors of the female reproductive tract
- Embryonal Rhabdomyosarcoma of the ovary or cervix
- Juvenile granulosa cell tumor
- Gynandroblastoma
- Cervix primitive neuroectodermal tumors
Kidney diseases
Cystic nephromas
Cystic nephroma (CN) is a non-life-threatening tumor that develops in the kidneys. It is the most common kidney-related symptom to develop in individuals with DICER-1 syndrome[1]. The estimate risk of developing a CN by age 10 years is ~5-10% for both male and female individuals with DICER-1 syndrome[5]. CN typically onsets in young children under the age of 4 years, however it has also been documented to develop in teenagers and in young adults. CN tumors are typically described as a mass made up of a large number of fluid-filled cysts. Symptoms include:
- lump felt in abdomen
- pain in abdomen or lower back
- blood in urine
- urinary tract infection
- fever
- fatigue
- anemia
Although CN is a benign tumor, there has been evidence that they may have an increase the chance of becoming cancerous[5]. CN tumors may also strain normal kidney function as they can often grow fairly quickly and become quite large. Early detection and surgical removal of the CN tumor is the most efficient method for preserving kidney function[3].
Kidney tumors
- Wilms Tumors
- Anaplastic sarcoma of kidney
Features affecting the head, neck and nervous system
Macrocephaly
Macrocephaly is defined as having a head circumference greater than the 97th percentile. It is estimated that macrocephaly is seen in 42% of DICER-1 carriers in early childhood[9]. It is typically diagnosed by the age of 5 years old. Macrocephaly has not been associated with any cognitive effects in individuals affected by DICER-1 syndrome.
Pituitary Blastoma
The pituitary gland is located right below the brain. It releases hormones into our blood stream and is responsible for controlling the hormone levels released by other organs, such as the ovaries, testes and the adrenal gland. This type of tumor is extremely rare in the general population, and is most often diagnosed in individuals who carry a DICER1 mutation[5]. Pituitary blastomas typically develop in infants and young children by the age of 2 years[4]. The most common symptoms include:
- Headache
- Vomiting
- Double vision
- Decreased vision and impaired eye movements (such as difficulties looking upwards)
- Altered walking
- Early onset of puberty
- Crushing syndrome (described as cortisol-related weight distribution, including round face, round stomach, and thin arms and legs)
Other head, neck and nervous system features
- Brain tumors
- Pineoblastoma
- Medulloblastoma
- Benign nasal tumors
- Nasal chondromesenchymal hamartoma (NCMH)
- Eye tumors
- Ciliary body medulloepothelioma (CBME)
- Eye anomalies have been identified in ~10% of individuals with DICER-1 syndrome[10]. Associated eye anomalies include:
- Congenital phtisis bulbi
- Pigmentary abnormalities
- Epiretinal membranes
- Drusen
- Retinitis pigmentosa
- Nervous system tumors
- Neuroblastoma
- Dental anomalies (eg. bulbous crowns) have been reported
Other rare features and tumors associated with DICER-1 syndrome
- Juvenile hamartomatous intestinal polyps
- Embryonal Rhabdomyosarcoma of the bladder
Clinical management of DICER-1 Syndrome
There is currently no cure for DICER-1 syndrome.
The clinical management for individuals affected with DICER-1 syndrome involved regular screening and surveillance of the systems of the body most commonly affected by features which can affect quality of life or are life-threatening. It is also recommended that patients be thoroughly educated on the signs and symptoms of DICER-1 syndrome associated features. The goal of this approach is to identify the development of a feature in it's early stages, when medical intervention is most effective.
Regular screening may alleviate some of the anxiety associated with DICER-1 syndrome and give some patients a sense of control, however this is not always the case. Some patients or caregivers may not feel relief, but rather a sense of frustration or exhaustion due to the high frequency of doctor appointments and scans. Individuals affected with DICER-1 syndrome should consult with their doctor to determine the best screening program to follow.
The recommendations below are from published guidelines by DICER-1 experts, however these are simply recommendations. The screening program can be altered to better suit an individual's needs based on their personal medical history, family history, access healthcare facilities and the feasibility of regular screening.
| System | Condition of interest | Minimum screening recommendations | Extended screening recommendations |
|---|---|---|---|
| General | - Annual clinic review for symptoms and clinical examination from birth to age 20 years | ||
| Lung | - PPB
- lung cysts - pulmonary blastomas |
- U/S during 3rd trimester of pregnancy
- Chest X-ray every 6 months from birth to age 6 years - Single chest X-ray at the time of diagnosis if DICER1 syndrome is diagnosed after age 6 years |
- Low-dose chest CT within first year of life
- Low-dose chest CT at age 2.5–3 years - Annual chest X-ray from age 8 years to age 12 years |
| Ovaries | - SLCT
- Gynandroblastoma - Embryonal rhabdomyosarcoma of the ovary or cervix |
- Education regarding symptoms recommended | - Annual U/S of the abdomen and pelvis, focusing on the ovaries from age 8 to age 40 years |
| Thyroid | - MNG
- Differentiated thyroid cancers |
- Thyroid U/S every 3 years from age 8 to age 40 years
- Thyroid function monitoring during pregnancy |
- Thyroid U/S at the time of diagnosis if DICER1 syndrome is diagnosed between 40 and 50 years old
- Annual neck palpation from age 8 to age 20 years |
| Kidney | - Cystic nephroma
- Kidney tumors |
- Abdominal US every 6 months from birth to age 6 to 8 years | - Single abdominal U/S at the time of diagnosis if DICER1 syndrome is diagnosed after annual screening is stopped
- Annual abdominal U/S until age 12 years |
| Head, neck
and brain (excluding thyroid) |
- Pituitary blastoma
- NCMH - Eye disorders, tumors or CBME - other associated brain tumors |
- Education regarding symptoms recommended
- Recommend urgent MRI for any symptoms of intracranial pathology |
- Physical exam
- Annual routine dilated ophthalmologic exam with visual acuity screening from age 3 years to age 10 years. |
Screening and surveillance recommendations for individuals with DICER-1 Syndrome listed above are based on published recommendations made by both the SIOPE Host Genome Working Group[4] and the International PPB Registry DICER1 Symposium to develop consensus testing[1][3]. Minimum screening recommendations are based on expert consensus. Extended screening recommendation column includes supplemental screening recommendations (in addition to the minimum recommendations) based on inconsistent evidence and limited expert agreement.
U/S = Ultrasound imaging
PPB = Pleuropulmonary Blastoma
SLCT = Sertoli-Leydig Cell tumor
MNG = Multinodular Goiter
NCHM = Nasal Chondromesenchymal Hamartoma
CBME = Ciliary body Medulloepithelioma
What causes DICER-1 syndrome?
Our body is made up of billions of cells. In each cell, there are sets of instructions which tells the cells how to develop and maintain our bodies. Each set of instruction is called a gene. Each human has the same set of instructions, the same number of genes, which results in a functioning human body. The reason that we are all a bit different is that we each have small differences in the ways that these instructions are written. We call this genetic variation. In some people, there is a spelling mistake, called a mutation, in a part of the instructions. This can cause the cells which make up the body to be unable to follow the instructions of that gene. These spelling mistakes, or mutations, can cause diseases like DICER-1 syndrome.
In DICER1 syndrome, there is a mutation in the DICER1 gene. The DICER1 gene is part of a group of genes which tells each cell which sets of instructions it should follow so that each cell performs the right task. It is similar to the director of the orchestra, instructing each instruments what part it should play, and when. Without the director, there is a greater chance that some cells will go rogue, and can begin to reproduce too much or too often. This is why there is an increased chance that individuals with a mutation in DICER1 will develop tumors. DICER1 plays a key role in regulating development, which is why most of the effects of DICER-1 syndrome are seen in children[4].
How common is DICER-1 syndrome?
It has been estimated that the prevalence of individuals who carry pathogenic mutations in the DICER1 gene is between 1:2500 and 1:11 000 [11][12]. Women and men can have DICER-1 syndrome at the same rates, however women are more likely to develop associated features. This is due to the fact that there is no sex preference for which individuals will inherit or develop a DICER1 mutation, however ovarian tumors can only occur in women, and the risk of developing thyroid-related features of DICER-1 syndrome are 3-fold higher in women compared to men[7].
How is DICER-1 syndrome diagnosed?
A diagnosis of DICER-1 syndrome is given if an individual is confirmed to carry a pathogenic mutation in the DICER1 gene. Individuals who are suspected to have DICER-1 syndrome can undergo genetic testing to determine if a mutation is present.
DICER-1 syndrome is associated with an increased risk for the development of the features and tumors listed above. Of the features listed above, some are quite common in the general population, such as adult-onset thyroid nodules. Individuals who only develop a single common adult-onset features are not highly suspicious cases for DICER-1 syndrome, unless accompanied with a significant family history of DICER-1 related features. Alternatively, other features of DICER-1 syndrome are extremely rare in the general population, such as PPB and childhood onset ovarian cancers (ex. SLCT). Individuals diagnosed with rare DICER-1 related features, develop several features of DICER-1 syndrome, or who develop associated features at a very young age should be offered genetic testing.
Inheritance of DICER-1 syndrome
Each individual has two copies of every gene in their body: one from their mother and one from their father.
DICER-1 syndrome is a type of genetic condition which follows a dominant inheritance pattern[2]. This means that only one of the two DICER1 genes need to have a mutation for an individual to have DICER-1 syndrome.
When an individual has children, they have an equal chance of passing on either copy of their DICER1 gene to each of their children. This means that each child of an individual with DICER-1 syndrome has a 50% chance of inheriting the gene copy that has a mutation. If a child inherits the mutation, they will also have DICER-1 syndrome.
Are my family members at risk?
There are two main ways for an individual to carry a mutation in the DICER-1 gene:
- Inherited: The mutation was passed down from a parent, and runs in the family
- New mutation: The mutation spontaneously appeared in the individual, and is not present in either parent
DICER-1 syndrome is most often an inherited genetic condition, meaning the mutation was passed down from a parent. About 80% of all individuals with DICER-1 syndrome inherited the condition from one of their two parents[2][13]. Due to this, DICER-1 syndrome tends to run in families. When an individual is identified as having DICER-1 syndrome, genetic testing is typically offered to all 1st degree relatives: the individual's siblings, mother, father, and children. If the DICER1 mutation was inherited, then each 1st degree relative of an individual with DICER-1 syndrome has a 50% chance of carrying the same mutation.
Less commonly, an individual is identified as having a mutation in the DICER-1 gene, but it is not present in either of their parents. This would indicated that the mutation is a new mutation (named de novo mutation) in this individual. In this situation, the only family members that are at risk of inheriting the mutation are the children of the affected individual. Approximately 20% of people diagnosed with DICER-1 syndrome have been found to carry new mutations[2].
Regardless of if the mutation is new in the individual or inherited, there is a 50% chance that their child will inherit the mutation. This risk is the same for each child of an affected individual, no matter if a previous child was affected or not.
Genetic counselling for DICER-1 Syndrome
Genetic counselling
Genetic counselling for DICER-1 syndrome can be offered by qualified professionals, such as a geneticist or a genetic counsellor, if an individual is suspected to have the condition due to a personal or family history of DICER-1 syndrome associated features. During a genetic counselling appointment, the healthcare professional will collect the individuals personal and medical history to assess the risk that the individual has DICER-1 syndrome, and order genetic testing if appropriate. Genetic counsellors are also trained to help individuals decide if genetic testing is right for them, and which type of testing would be most appropriate. Genetic counselling sessions typically also include an educational portion, where the counsellor or physician will go over the features associated with DICER-1 syndrome in more detail, and discuss the potential next steps if a DICER-1 syndrome diagnosis was confirmed. Genetic counsellors are also well equipped to provide individuals with resources or connect them with other care professionals or support groups.
Individuals with DICER-1 syndrome should consult a genetic counsellor to discuss family planning, prenatal genetic testing of an ongoing pregnancy, and options for pre-implantation genetic testing.
Genetic testing
Genetic testing can be done from either a blood sample, a saliva sample, or, less commonly, a tissue sample (ex. biopsy) from the individual. The sample would be sent to a molecular genetic laboratory where it will be processed and analyse to determine whether a mutation is present or not. The lab will be able to identify the mutation, or the spelling mistake, by comparing the spelling of the DICER1 gene from the individual to a set of references. These references include many of the normal genetic variations seen in the population. If there is a change in the DICER1 gene that is not expected, further studies will be done to determine whether the change in the gene is a harmless gene variation, or if it is a disease-causing mutation. There are 3 types of results that are possible from genetic testing:
- Positive result: This result means that a disease-causing (pathogenic) mutation in the individual's DICER1 gene was identified, and a diagnosis of DICER-1 syndrome is supported. Individuals identified as being positive for a pathogenic mutation in DICER1 are at risk of developing the features of DICER-1 syndrome, and should consult their physician to determine how to best manage their risk.
- Negative result: This result means that the DICER1 gene was spelled correctly, and does NOT support a DICER-1 syndrome diagnosis. No changes to clinical management should be made based on these results.
- Variant of Uncertain Significance (VUS): These results indicate that there was a difference in the spelling of the DICER1 gene identified, however it is unknown if the change is harmless (benign) or disease-causing (pathogenic). Individuals will receive these results because their DICER1 gene is spelled in a way that is very rare or has never been seen before. It simply means that it is unsure what the effects of the change could be. Most of the time, studies will show that the change is simply harmless genetic variation. Due to this, individuals identified with a VUS should be treated as though the result of the genetic test was negative. No change in clinical management should be made based on these results. Note: VUS results are more commonly identified in individuals who are not of European ancestry.
It is important to note that careful considerations should be made prior to having genetic testing done, at this is a very personal decision.
Who will be affected by the features of DICER-1 syndrome?
Penetrance is a term used to describe the proportion of individuals who carry a pathogenic genetic mutation that will be affected by the syndrome, meaning they develop at least one associated feature of the disease. DICER-1 syndrome has incomplete penetrance. This means that having a diagnosis of DICER-1 syndrome does not guarantee that an individual will be affected. This syndrome is characterized by an increased chance for developing the associated features listed above, not a guarantee. Even within families carrying the same genetic change, there can be a wide range in the severity of symptoms and many individuals within a family will never be affected. Science is not yet able to predict if an individual will be affected, or how DICER-1 syndrome will manifest in a given person.
The most common presentation of DICER-1 syndrome is the development of nodules in the thyroid or multinodular goiter (MNG). For individuals who have DICER-1 syndrome, it is estimated that nearly 75% of women will develop MNG or need a thyroidectomy by the age of 40 years. This estimate for men is much lower, with a ~17% risk[7].
For the more dangerous features of DICER-1 syndrome, such as cancers and tumors, the risk is much lower. The risk of developing a DICER-1 associated cancer or tumor is also known to decrease as a person ages. It has been estimated that approximately 5% of individuals with DICER-1 syndrome will develop a cancer or tumor by the age of 10 years old. The risk for developing a DICER-1 syndrome related cancer or tumor by the age of 50 is approximately 25% for women, and 10% for men[4][5].
Patient resources
Information on DICER-1 Syndrome patient registries
Patient registries webpages include information about DICER-1 syndrome. They also provide contact information for patients to enroll in the registry, which may allow them to participate in DICER-1 syndrome clinical research, depending on the criteria of on-going studies. Patients enrolled in registry or they treating physician may also be contacted by researchers to be informed of up-to-date screening recommendations and treatment guidelines.
Support groups and community
Patients often feel a sense of isolation after receiving a diagnosis of a rare disease, such as DICER-1 syndrome. Many find comfort in reading about the stories of other individuals affected by a similar condition, or in joining online support groups. Support group and patient testimonies can be found on patient registry websites listed above, or on the Children's Cancer Network website.
Finding a genetic counsellor near you
Another helpful way to find a support community near you would be to speak to a local genetic counsellor. Genetic counsellors can help patients understand their diagnosis, and may be helpful in providing additional resources to their patients.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Schultz, K.A.P., Rednam, S.P., Kamihara, J., Doros, L., Achatz, M.I., Wasserman, J.D., Diller, L.R., Brugières, L., Druker, H., Schneider, K.A., McGee, R.B., Foulkes, W.D. (2017). PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clin Cancer Res; 23 (12): e76–e82. https://doi.org/10.1158/1078-0432.CCR-17-0629
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Schultz KAP, Stewart DR, Kamihara J, et al. (2014). DICER1 Tumor Predisposition. [Updated 2020 Apr 30]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK196157/
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Schultz, K. A. P., Williams, G. M., Kamihara, J., Stewart, D. R., Harris, A. K., Bauer, A. J., Turner, J., Shah, R., Schneider, K., Schneider, K. W., Carr, A. G., Harney, L. A., Baldinger, S., Frazier, A. L., Orbach, D., Schneider, D. T., Malkin, D., Dehner, L. P., Messinger, Y. H., & Hill, D. A. (2018). DICER1 and Associated Conditions: Identification of At-risk Individuals and Recommended Surveillance Strategies. Clinical cancer research : an official journal of the American Association for Cancer Research, 24(10), 2251–2261. https://doi.org/10.1158/1078-0432.CCR-17-3089
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Bakhuizen, J. J., Hanson, H., van der Tuin, K., Lalloo, F., Tischkowitz, M., Wadt, K., Jongmans, M. C. J., SIOPE Host Genome Working Group, CanGene-CanVar Clinical Guideline Working Group, & Expert Network Members (2021). Surveillance recommendations for DICER1 pathogenic variant carriers: a report from the SIOPE Host Genome Working Group and CanGene-CanVar Clinical Guideline Working Group. Familial cancer, 20(4), 337–348. https://doi.org/10.1007/s10689-021-00264-y
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Stewart, D. R., Best, A. F., Williams, G. M., Harney, L. A., Carr, A. G., Harris, A. K., Kratz, C. P., Dehner, L. P., Messinger, Y. H., Rosenberg, P. S., Hill, D. A., & Schultz, K. A. P. (2019). Neoplasm Risk Among Individuals With a Pathogenic Germline Variant in DICER1. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 37(8), 668–676. https://doi.org/10.1200/JCO.2018.78.4678
- ↑ 6.0 6.1 Messinger, Y. H., Stewart, D. R., Priest, J. R., Williams, G. M., Harris, A. K., Schultz, K. A., Yang, J., Doros, L., Rosenberg, P. S., Hill, D. A., & Dehner, L. P. (2015). Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry. Cancer, 121(2), 276–285. https://doi.org/10.1002/cncr.29032
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 Khan, N. E., Bauer, A. J., Schultz, K. A. P., Doros, L., Decastro, R. M., Ling, A., Lodish, M. B., Harney, L. A., Kase, R. G., Carr, A. G., Rossi, C. T., Field, A., Harris, A. K., Williams, G. M., Dehner, L. P., Messinger, Y. H., Hill, D. A., & Stewart, D. R. (2017). Quantification of Thyroid Cancer and Multinodular Goiter Risk in the DICER1 Syndrome: A Family-Based Cohort Study. The Journal of clinical endocrinology and metabolism, 102(5), 1614–1622. https://doi.org/10.1210/jc.2016-2954.
- ↑ Chernock, R. D., Rivera, B., Borrelli, N., Hill, D. A., Fahiminiya, S., Shah, T., Chong, A. S., Aqil, B., Mehrad, M., Giordano, T. J., Sheridan, R., Rutter, M. M., Dehner, L. P., Foulkes, W. D., & Nikiforov, Y. E. (2020). Poorly differentiated thyroid carcinoma of childhood and adolescence: a distinct entity characterized by DICER1 mutations. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 33(7), 1264–1274. https://doi.org/10.1038/s41379-020-0458-7
- ↑ Khan, N. E., Bauer, A. J., Doros, L., Schultz, K. A., Decastro, R. M., Harney, L. A., Kase, R. G., Carr, A. G., Harris, A. K., Williams, G. M., Dehner, L. P., Messinger, Y. H., & Stewart, D. R. (2017). Macrocephaly associated with the DICER1 syndrome. Genetics in medicine : official journal of the American College of Medical Genetics, 19(2), 244–248. https://doi.org/10.1038/gim.2016.83
- ↑ Huryn, L. A., Turriff, A., Harney, L. A., Carr, A. G., Chevez-Barrios, P., Gombos, D. S., Ram, R., Hufnagel, R. B., Hill, D. A., Zein, W. M., Schultz, K. A. P., Bishop, R., & Stewart, D. R. (2019). DICER1 Syndrome: Characterization of the Ocular Phenotype in a Family-Based Cohort Study. Ophthalmology, 126(2), 296–304. https://doi.org/10.1016/j.ophtha.2018.09.038
- ↑ Kim, J., Field, A., Schultz, K. A. P., Hill, D. A., & Stewart, D. R. (2017). The prevalence of DICER1 pathogenic variation in population databases. International journal of cancer, 141(10), 2030–2036. https://doi.org/10.1002/ijc.30907
- ↑ Kim, J., Schultz, K. A. P., Hill, D. A., & Stewart, D. R. (2019). The prevalence of germline DICER1 pathogenic variation in cancer populations. Molecular genetics & genomic medicine, 7(3), e555. https://doi.org/10.1002/mgg3.555
- ↑ de Kock, L., Wu, M. K., & Foulkes, W. D. (2019). Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes. Human mutation, 40(11), 1939–1953. https://doi.org/10.1002/humu.23877