NORD gratefully acknowledges Shashikant Kulkarni, PhD, Director of CytoGenomics and Molecular Pathology, Director of Clinical & Molecular Cytogenetics, Department of Pathology, Washington University School of Medicine, for assistance in the preparation of this report.
Chromosome 18 Ring is a rare disorder in which there is loss (deletion) of genetic material from one or both ends of the 18th chromosome and joining of the chromosomal ends to form a ring. Associated symptoms and findings may vary greatly in range and severity from case to case, depending upon the amount and location of lost genetic material and other factors. A ring may also be formed without the loss of any genetic material. However, many individuals with the disorder are affected by mental retardation; low muscle tone (hypotonia); growth retardation; repeated infections during the first years of life; and/or malformations of the skull and facial (craniofacial) region. Such craniofacial features often include an unusually small head (microcephaly), widely spaced eyes (ocular hypertelorism), and/or vertical skin folds that cover the eyes' inner corners (epicanthal folds). Chromosome 18 Ring is usually caused by spontaneous (de novo) errors very early in the development of the embryo that appear to occur randomly for unknown reasons (sporadically).
As mentioned above, associated symptoms and physical features may be extremely variable. For example, there have been a few cases in which individuals with Chromosome 18 Ring have few or no apparent symptoms. However, others with the chromosomal abnormality may have multiple, severe features of the disorder. In most affected individuals, characteristic features include moderate to severe mental retardation; growth delays; poor muscle tone (hypotonia); craniofacial malformations; eye abnormalities; and/or an increased susceptibility to certain infections.
In individuals with Chromosome 18 Ring, craniofacial abnormalities often include an unusually small head (microcephaly); a highly arched roof of the mouth (palate); and a short upper lip with an outwardly turned (everted) lower lip, producing a distinctive, “carp-shaped” mouth. Additional craniofacial features may include an unusually small or protruding lower jaw (micrognathia or prognathism) and/or an undersized tongue (microglossia). Affected individuals may also have low-set, malformed (dysplastic) ears and/or narrow (stenotic) or absent (atretic) ear canals, with associated hearing impairment.
Reports indicate that over half of affected individuals also have eye (ocular) abnormalities. Such ocular defects may include widely spaced eyes (ocular hypertelorism); vertical skin folds over the inner angles of the eyes (epicanthal folds); drooping of the upper eyelids (ptosis); and/or abnormal deviation of one eye in relation to the other (strabismus). Some affected individuals may also have involuntary, rhythmic, rapid eye movements (nystagmus); abnormally small eyes (microphthalmia); and/or partial absence of the iris or the colored region of the eyes (aniridia).
Investigators indicate that up to 50 percent of individuals with Chromosome 18 Ring have low levels of a particular antibody (i.e., immunoglobulin A [IgA]), resulting in an increased susceptibility to certain infections during the first years of life. Rare cases have also been reported in which affected individuals have low levels of other immunoglobulins (e.g., IgG, IgM).
Chromosome 18 Ring may also be characterized by skeletal abnormalities, such as rib and/or spinal column (vertebral) defects; unusually small or short arms and legs (micromelia); abnormal deviation (clinodactyly) of the “pinkies” or fifth fingers; and/or overlying toes. Additional physical features reported in association with the disorder have included widely spaced, underdeveloped nipples; a low hair line; webbing of the neck; genital abnormalities; structural malformations of the heart (congenital heart defects); and/or kidney (renal) defects. In addition, some researchers indicate that Chromosome 18 Ring may be associated with an increased predisposition to autoimmune thyroiditis. Also known as Hashimoto’s thyroiditis, this condition is characterized by inflammation of the thyroid gland (thyroiditis) due to an abnormal immune reaction in which the body produces antibodies improperly directed against the thyroid. (For further information, please choose “Hashimoto*” as your search term in the Rare Disease Database.)
A few severe cases have also been reported in which Chromosome 18 Ring has been associated with holoprosencephaly. This is an extremely rare condition in which the forebrain (prosencephalon) fails to divide properly into hemispheres during embryonic development, resulting in malformations of the center (midline) of the brain and the craniofacial region. Associated findings may be extremely variable. Some affected individuals may have an abnormally small head (microcephaly), closely set eyes (hypotelorism), absence of certain front teeth (incisors), incomplete closure of the roof of the mouth (cleft palate), an abnormal groove in the upper lip (cleft lip), and/or other abnormalities. Severely affected individuals may have additional abnormalities, such as malformation or absence of the nose and/or fusion of the orbits into a single eye cavity containing one eye (cyclopia). (For further information on this condition, please choose “holoprosencephaly” as your search term in the Rare Disease Database.)
Chromosome 18 Ring results from loss (deletion) of genetic material from one or both ends of the 18th chromosome and a joining of the ends to form a ring. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered.
In individuals with Chromosome 18 Ring, the range and severity of associated symptoms and findings may be extremely variable, depending upon the amount and specific location of genetic material lost from the 18th chromosome, the stability of the ring chromosome during subsequent cellular divisions, or other factors. Some investigators suggest that certain characteristic features seen in Chromosome 18 Ring may result from deletions of genetic material at specific locations on the short and long arms of chromosome 18 (e.g., 18p11; 18q23), with the ring chromosome replacing a normal 18th chromosome. In addition, in some cases, only a percentage of an individual’s cells may contain Chromosome 18 Ring, while other cells may have a normal chromosomal makeup (a finding known as “chromosomal mosaicism”), potentially affecting the variability of associated symptoms and findings. Most reports in which individuals have demonstrated few or minor features of the disorder have been associated with a Chromosome 18 Ring mosaicism.
In most cases, Chromosome 18 Ring appears to be caused by spontaneous (de novo) errors very early in embryonic development. In such instances, the parents of the affected child usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality.
However, there have been some cases in which a parent of an affected individual also has Chromosome 18 Ring in all or some cells. In such instances, it is believed that Chromosome 18 Ring may have been inherited and that the chances are greater of having another child with the chromosomal abnormality.
Chromosomal analysis and genetic counseling are typically recommended for parents of an affected child to help confirm or exclude the presence of Chromosome 18 Ring or potential mosaicism.
Since Chromosome 18 Ring was originally described, more than 70 cases have been reported in the medical literature. In these observed cases, females appear to be affected slightly more often than males. The disorder is often detected at birth or during prenatal testing.
Ultrasound will indicate that something unusual is happening to the fetus. The diagnosis of Chromosome 18 Ring is made before birth (prenatally) by specialized tests such as amniocentesis, and/or chorionic villus sampling (CVS). During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing certain findings that suggest a chromosomal disorder or other developmental abnormalities in the fetus. During fetal blood sampling, blood is drawn with a needle that is guided via ultrasound into the umbilical vein. With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal analysis performed on such fluid or tissue samples may reveal the presence of Chromosome 18 Ring.
The disorder may also be diagnosed or confirmed after birth (postnatally) based upon a thorough clinical evaluation, detection of characteristic physical findings, and chromosomal analysis. Specialized tests may also be performed to help detect and/or characterize certain abnormalities that may be associated with the disorder.
The treatment of Chromosome 18 Ring is directed toward the specific symptoms that are apparent in each individual. In some cases, physicians may recommend surgical repair of certain craniofacial, skeletal, ocular, auditory, and/or other malformations potentially associated with the disorder. The specific surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.
For affected individuals with hearing loss, recommended treatment may include surgical measures and/or the use of specialized hearing aids or additional supportive techniques that may aid communication. In those with ocular abnormalities, corrective lenses, surgery, and/or other measures may be used to help improve vision in some cases. In addition, for individuals with low levels of certain antibodies (e.g., IgA), disease management includes ongoing monitoring and appropriate, supportive measures to help prevent and aggressively treat infections.
Early intervention may be important in ensuring that affected children reach their potential. Special services that may be beneficial include special education, physical therapy, speech therapy, and/or other medical, social, and/or vocational services. Genetic counseling will also be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., mental retardation, craniofacial abnormalities, ocular defects, ear malformations and hearing impairment, etc.].)
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