Information on the following diseases can be found in the Related Disorders section of this report:

• Wolf-Hirschhorn Syndrome
• Chromosomal Disorders (General)

As noted above, associated symptoms and physical findings may be extremely variable from case to case. Some infants with Chromosome 4 Ring 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, 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). (For further information on this disorder, please see the "Related Disorders" section of this report below.) Investigators indicate that others with Chromosome 4 Ring may have few symptoms and be primarily affected by growth delays (failure to thrive), with no major physical anomalies.

In some infants and children, Chromosome 4 Ring 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 Chromosome 4 Ring may have normal intelligence and normal psychomotor development.

Craniofacial malformations associated with Chromosome 4 Ring 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 Chromosome 4 Ring is associated with underdevelopment of the kidneys at birth (congenital renal hypoplasia). Known as oligomeganephronia, the condition is characterized by decreased numbers of the filtering units (nephrons) of both kidneys, with "compensatory" enlargement (i.e., hypertrophy) of the nephrons that are present. Oligomeganephronia 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, Chromosome 4 Ring may also be associated with additional congenital anomalies.

In most affected individuals, Chromosome 4 Ring 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 Chromosome 4 Ring, 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 Chromosome 4 Ring appear to result from deletions of genetic material at 4p16. In addition, in some cases, only some of an individual's cells may contain Chromosome 4 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.

Researchers have also reported cases in which Chromosome 4 Ring is present with no detectable loss of genetic material (as based upon chromosomal analysis). Such cases are sometimes referred to as so-called "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, Chromosome 4 Ring 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 Chromosome 4 Ring, 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.)
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Since Chromosome 4 Ring was originally described, more than 20 cases have been reported in the medical literature. Males and females appear to be affected relatively equally.

Symptoms of the following disorders may be similar to those of Chromosome 4 Ring. Comparisons may be useful for a differential diagnosis:

Wolf-Hirschhorn syndrome, also known as Wolf syndrome, is a rare chromosomal disorder in which there is partial deletion (monosomy) of the short arm (p) of chromosome 4 (4p). Although the size and location of the 4p deletion vary from case to case, it is believed that deletion of band 4p16.3 is the critical region leading to characteristic features of the disorder. Associated abnormalities typically include a low birth weight, growth retardation, poor muscle tone (hypotonia), and delays in the acquisition of skills requiring the coordination of physical and mental activities (psychomotor retardation). Most affected infants and children also have distinctive malformations of the skull and facial (craniofacial) region. These may include a small head (microcephaly) and high forehead; highly arched eyebrows; widely spaced eyes (ocular hypertelorism); vertical skin folds that cover the eyes' inner corners (epicanthal folds); a "beaked" nose with an abnormally wide nasal bridge; a downturned mouth; an unusually short vertical groove in the middle of the upper lip (philtrum); and/or large, malformed ears. Due to these and/or additional craniofacial malformations, the face may appear relatively dissimilar from one side to the other (craniofacial asymmetry). Additional physical abnormalities may also be present. Such features may include abnormal deviation of one eye in relation to the other (strabismus); partial absence of tissue from the colored region of the eye (iris coloboma); incomplete closure of the roof of the mouth (cleft palate); undescended testes (cryptorchidism) and abnormal placement of the urinary opening on the underside of the penis (hypospadias) in affected males; structural malformations of the heart; sudden episodes of uncontrolled electrical activity in the brain (seizures); skeletal abnormalities; and/or other findings. Wolf-Hirschhorn syndrome usually appears to occur spontaneously (de novo) for unknown reasons very early in embryonic development. Less commonly, it may appear to result from a balanced translocation in one of the parents.

Additional chromosomal disorders may have features similar to those associated with Chromosome 4 Ring. Chromosomal testing is necessary to confirm the specific chromosomal abnormality present. (For further information on such disorders, choose the name of the specific chromosomal disorder in question or use "chromosome" as your search term in the Rare Disease Database

Diagnosis
In some cases, Chromosome 4 Ring 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 Chromosome 4 Ring.

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.

Treatment
The treatment of Chromosome 4 Ring 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.

Research on birth defects and their causes is ongoing. The National Institutes of Health (NIH) is sponsoring the Human Genome Project which is aimed at mapping every gene in the human body and learning why they sometimes malfunction. It is hoped that this new knowledge will lead to prevention and treatment of genetic disorders in the future.

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
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

TEXTBOOKS
Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Company; 1997:38-39.

Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:317.

Gorlin RJ, et al., eds. Syndromes of the Head and Neck. 3rd ed. New York, NY: Oxford University Press; 1990:46-48.

Buyse ML. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, Inc.; 1990:336-37.

JOURNAL ARTICLES
Sigurdardottir S, et al. Clinical, cytogenetic, and fluorescence in situ hybridization findings in two cases of "complete ring" syndrome. Am J Med Genet. 1999;87:384-90.

Anderson CE, et al. Ring chromosome 4 mosaicism coincidence of oligomeganephronia and signs of Seckel syndrome. Am J Med Genet. 1997;72:281-85.

Park SH, et al. Oligomeganephronia associated with 4p deletion type chromosomal anomaly. Pediatr Pathol. 1993;13:731-40.

Pezzolo A, et al. Presence of telomeric and subtelomeric sequences at the fusion points of ring chromosomes indicates that the ring syndrome is caused by ring instability. Hum Genet. 1993;92:23-27.

Giuffre L, et al. Ring chromosome 4 in twins. Pediatr Med Chir. 1987;9:349-50.

Gutkowska A, et al. Ring chromosome 4 : 46,XY, r(4) (p16q35) in a boy. Klin Padiatr. 1985;197:294-96.

Kosztolanyi G. Ring chromosome 4: Wolf syndrome and unspecific developmental anomalies. Acta Paediatr Hung. 1985;26:157-65.

Haspeslagh M, et al. Severe limb malformations in 4p deletion. Clin Genet. 1984;25:353-56.

del Mazo J, et al. Partial deletion of 4p16 band in a ring chromosome and Wolf Syndrome. Hum Genet. 1978;44:105-08.

Perez-Castillo A, et al. Ring chromosome 4 and Wolf syndrome. Hum Genet. 1977;37:87-91.