DICER1 Syndrome: Genetics, Inheritance and Key Clinical Features
DICER1 syndrome is a familial tumor predisposition syndrome that results from genetic mutations in a gene called DICER1. Some tumors of DICER1 syndrome are very serious and life threatening, but many of the tumors are not nearly that serious. In general, the tumors are rare or very rare, and some are so rare that they may occur only in individuals with a DICER1 mutation.
There appears to be no pattern to the development of tumors, except that each tumor in DICER1 syndrome tends to occur at certain typical ages for that tumor. Those who develop the various tumors associated with DICER1 syndrome tend to do so in childhood, even infancy, or by the age of about 30 years old. It is estimated that more than half of the individuals with DICER1 syndrome have no medical problems. While individuals with DICER1 syndrome are at increased risk for developing the tumors recognized in this website, most people with DICER1 syndrome will never develop a tumor.
Pleuropulmonary blastoma (PPB) is a rare, malignant, early-childhood lung tumor. It was first recognized by doctors in about 1985. Of course, PPB occurred before 1985 but was so rare that doctors had never recognized it as a distinct illness. PPB is completely different from and has no relationship to lung cancer in adults. Because this rare disease occurred in some families, the search for a cause led to the discovery of DICER1 mutations, which are now known to cause the vast majority of PPB cases.
Thyroid Disease in DICER1 Syndrome
The thyroid gland is the site of the most frequent abnormalities associated with DICER1 mutations. The gland is located in the front of the neck just below the voice-box (“Adam’s apple”) and has butterfly-wing-shaped lobes on each side of the windpipe as shown in the adjacent diagram
The thyroid gland produces a hormone which controls many actions in the body which can be generally described as setting the body’s energy thermostat. Too much thyroid hormone and the body goes too fast with weight loss and a tendency to feel too warm; too little thyroid hormone and the body slows down with feeling cold, weight gain and constipation. The thyroid conditions in DICER1 syndrome, described below, do not alter thyroid hormone activity.
In DICER1 syndrome, the hormone control function of the gland is not affected, but benign lumps (tumors) can appear in the gland enlarging it with visible swelling across the lower front of the neck called “goiter”. The lumps are rarely malignant.
Pituitary Blastoma in DICER1 Syndrome
Kidney Cysts and Tumors in DICER1 Syndrome
The kidneys are the main organs of the urinary system. They serve multiple vital purposes including the elimination of toxins that leave the body in the form of urine. Kidney cysts and tumors have been observed in a number of patients with DICER1 syndrome.
Ovarian Sertoli-Leydig Cell Tumor and Other Female Reproductive Tract Tumors in DICER1 Syndrome
One tumor of the ovary (Sertoli-Leydig cell tumor) is among the frequent manifestations of DICER1 mutation in females. Another ovarian tumor and a tumor of the uterine cervix (called embryonal rhabdomyosarcoma) are very rare manifestations of DICER1 mutation.
Miscellaneous Unusual Tumors in DICER1 Syndrome
One of the most distinctive overall features of DICER1 syndrome is that mutation carriers are susceptible to very unusual conditions. Although these conditions are rare in general, they nevertheless occur in this syndrome with what appears to be increased frequency. Though they seem to occur more frequently in DICER1 syndrome than in the general population, these conditions remain unusual in the syndrome.
In addition to the unusual tumors discussed in other sections, three other rare conditions are discussed here:
- Eye tumor: “Ciliary body medulloepithelioma”
- Nasal sinus tumor: “Nasal chondromesenchymal hamartoma”
- Polyps in the intestinal tract: “Juvenile hamartomatous polyps”
Ciliary Body Medulloepithelioma
Ciliary body medulloepithelioma (CBME) is a small tumor in the front of the eye. The “ciliary body” is a tiny, complex ring-shaped structure inside and at the front of the eyeball surrounding the lens. Muscles in the ciliary body control the shape of the lens and other parts of the ciliary body carry blood vessels to supply and control the inner contents of the eye. “Medulloepithelioma” is a very complex pathologist’s term to describe the microscopic appearance of certain kinds of abnormal tissue. CBME can be malignant or benign – to date, the very few CBME which have been associated with DICER1 mutation have been benign.
CBMEs in DICER1 syndrome have occurred in children under 10 years of age. Fewer than 20 cases connected to DICER1 have been reported in the medical literature, so it is very unusual even in DICER1 syndrome
Nasal Chondromesenchymal hamartoma
Like many tumors associated with DICER1 mutations, nasal chondromesenchymal hamartoma (NCMH) is very unusual, yet it occurs sometimes in DICER1 syndrome. It occurs in the nasal cavity and the sinuses adjacent to the nasal cavity. (Sinuses are essentially air-filled cul-de-sacs, or “out-croppings”, attached to the nasal cavity. Sinuses make various facial bones lighter in weight by creating air-filled pockets within them.)
NCMH is a benign tumor – a benign growth. It is named by pathologists for its appearance under the microscope: “chondromesenchymal” means that the tissue has features of cartilage and other connective tissues. The word hamartoma is quite difficult to define but generally means that the tumor material looks fairly normal, but there is too much of it.
NCMH may be bilateral – that is, affect right and left sinuses at the same time. As an NCMH tumor enlarges, it can push aside and distort small facial bones, but it pushes them (instead of invading them), which is consistent with the concept that NCMH is not malignant.
Juvenile Intestinal Polyps
Juvenile intestinal polyps are small grape size lumps or clusters growing from the inside surface of the intestinal tube. Although named ‘juvenile’ polyps because of a specific appearance under the microscope, these polyps tend to occur not only in early childhood but up to the ages of 15-20 years. They may partially block the intestine, slowing the passage of intestinal contents. They are benign. There is likely to be only one or a few polyps. They occur in the general population as well as in DICER1 syndrome. They are unusual in DICER1 syndrome, and although proof does not yet exist that they are directly connected to DICER1 mutation, it appears as if there is a connection.
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