Ring chromosome 4 is a rare disorder that is typically characterized by loss (deletion) of genetic material from both ends of the 4th chromosome and joining of the chromosomal ends to form a ring. Associated symptoms and findings may vary greatly, depending on the location of lost genetic material and/or other factors. Some affected infants may have a low birth weight; growth retardation; delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation); an abnormally small head (microcephaly); a broad, "beaked" nose; and/or various additional physical abnormalities that are present at birth (congenital anomalies). However, cases have also been reported in which ring chromosome 4 is primarily associated with growth retardation, with no major physical anomalies and normal psychomotor development. Ring chromosome 4 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 noted above, associated symptoms and physical findings may be extremely variable from case to case. Some infants with ring chromosome 4 may have multiple characteristic features, such as a low birth weight, feeding difficulties, failure to grow and gain weight at the expected rate (failure to thrive), developmental delays, malformations of the skull and facial (craniofacial) region, heart defects, and/or other physical abnormalities. In addition, certain features may be similar to those seen in individuals with Wolf-Hirschhorn syndrome, which is a chromosomal disorder characterized by partial deletion (monosomy) of the short arm (p) of chromosome 4 (partial monosomy 4p) or features similar to those seen in individuals with partial deletion (monosomy) of the long arm (q) of chromosome 4 (partial monosomy 4q. (For further information on this disorder, please see the “Related Disorders” section of this report below.) Investigators indicate that others with ring chromosome 4 may have few symptoms and be primarily affected by growth delays (failure to thrive), with no major physical anomalies.
In some infants and children, ring chromosome 4 may be associated with mental retardation and delays in the development of physical, mental, and behavioral skills that are typically acquired at particular stages (developmental milestones). For example, there are usually delays in language and speech development. However, others with ring chromosome 4 may have normal intelligence and normal psychomotor development.
Craniofacial malformations associated with ring chromosome 4 may include an unusually small head (microcephaly); a broad, rounded, or “beaked” nose; a small jaw (micrognathia); and/or malformed (dysplastic) ears. In some cases, other craniofacial abnormalities may also be present, such as incomplete closure of the roof of the mouth (cleft palate), drooping of the upper eyelids (ptosis), and/or other findings.
Some affected individuals may also have abnormal bending or deviation of one or more fingers (clinodactyly); abnormal skin ridge patterns on the palms of the hands (palmar creases); and/or, in affected males, abnormal placement of the urinary opening on the underside of the penis (hypospadias). There have also been a few reports in which ring chromosome 4 is associated with underdevelopment of the kidneys at birth (congenital renal hypoplasia) or a missing kidney (renal agenesis). These conditions may lead to chronic renal failure or an impaired ability of the kidneys to excrete waste products through urine, regulate the balance of salt and water in the body, and perform their other vital functions. In addition, in some cases, ring chromosome 4 may also be associated with additional congenital anomalies.
In most affected individuals, ring chromosome 4 appears to result from loss (deletion) of genetic material from both ends of the 4th 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”, a long arm identified by the letter “q” and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, “chromosome 4p16″ refers to band 16 on the short arm of chromosome 4.
In individuals with ring chromosome 4, the variability of associated symptoms and findings may depend upon the location of genetic material lost from the 4th chromosome, the percentage of cells containing the chromosomal abnormality (see below*), the stability of the ring chromosome during subsequent cellular divisions (mitosis), and/or other factors. For example, reports indicate that affected individuals with deletions of chromosome 4q35 and 4p16 have similar symptoms and findings to those with deletions of 4q33 and 4p16. According to investigators, such findings suggest that certain features often seen in those with ring chromosome 4 appear to result from deletions of genetic material at 4p16. In addition, in some cases, only some of an individual’s cells may contain ring chromosome 4, while other cells may have a normal chromosomal makeup (a finding known as “chromosomal mosaicism*”), potentially affecting the variability of associated symptoms and findings.
Researchers have also reported cases in which ring chromosome 4 is present with no detectable loss of genetic material (as based upon chromosomal analysis). Such cases are sometimes referred to as “ring syndrome,” a general term used to describe the presence of growth retardation in the absence of major malformations due to a ring chromosome. Investigators suggest that such ring chromosomes originate with abnormal fusion of the ends (i.e., telomeres) of a particular chromosome (e.g., chromosome 4) and that “ring syndrome” results due to instability of the ring chromosome during subsequent cellular divisions.
In most cases, ring chromosome 4 appears to be caused by spontaneous (de novo) errors very early in embryonic development. In such cases, the parents of the affected child usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality. However, chromosomal analysis and genetic counseling are typically recommended for parents of an affected child to help confirm or exclude the presence of certain chromosomal abnormalities in one of the parents, such as ring chromosome 4, potential mosaicism, or a “balanced translocation” involving chromosome 4. (Translocations occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. If a chromosomal rearrangement is balanced, meaning that it consists of an altered but balanced set of chromosomes; it is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s offspring.)
Since ring chromosome 4 was originally described, close to 40 cases have been reported in the medical literature. Males and females appear to be affected relatively equally.
In some cases, ring chromosome 4 may be suggested before birth (prenatally) by specialized tests such as ultrasound, 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 abnormalities in the fetus. 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 ring chromosome 4.
The disorder may be diagnosed or confirmed after birth (postnatally) based upon 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 ring chromosome 4 is directed toward the specific symptoms that are apparent in each individual. In some cases, physicians may recommend surgical repair of certain 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.
Early intervention may be important in ensuring that affected children reach their potential. Special services that may be beneficial include special education, 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.
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