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NORD is very grateful to 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 8, Monosomy 8p is a rare chromosomal disorder characterized by deletion (monosomy) of a portion of the eighth chromosome. Associated symptoms and findings may vary greatly in range and severity from case to case. However, common features include growth deficiency; mental retardation; malformations of the skull and facial (craniofacial) region, such as a small head (microcephaly) and vertical skin folds that may cover the eyes' inner corners (epicanthal folds); heart (cardiac) abnormalities; and/or genital defects in affected males. Additional craniofacial features may also be present that tend to become less apparent with age, such as a short, broad nose; a low, wide nasal bridge; and/or a small jaw (micrognathia). In most cases, Chromosome 8, Monosomy 8p appears to result from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons.
As noted above, associated features may be extremely variable. However, in many cases, there are growth delays during fetal development (intrauterine growth retardation) as well as after birth (postnatal growth retardation).
The syndrome is also commonly associated with mild mental retardation, although more severe retardation may be seen in some instances. In addition, other cases have been described in which affected individuals have normal intelligence. Monosomy 8p may also be characterized by delays in the acquisition of skills that require the coordination of mental and motor activities (psychomotor retardation). According to reports in the medical literature, many affected children may have speech difficulties. In addition, behavioral problems are commonly seen during childhood, such as abnormally active (hyperactive), impulsive behavior and/or outbursts of aggressiveness.
Monosomy 8p is also typically characterized by craniofacial malformations that may be relatively subtle in some cases. In addition, a few cases have been reported in which such malformations are not apparent. Craniofacial features commonly seen with the syndrome include an unusually small head (microcephaly); a narrow skull and high forehead; low-set and/or malformed ears; and/or vertical skin folds that may cover the eyes' inner corners (epicanthal folds). As noted above, additional craniofacial abnormalities may also be present that may become less evident with age. Such features may include a flat, wide nasal bridge; a broad, short nose; a small, receding jaw (microretrognathia); and/or other abnormalities.
In addition, many affected individuals may have an unusually short neck; a broad chest; and/or widely set, underdeveloped (hypoplastic) nipples. Males with the syndrome may also have genital abnormalities, such as a developmental defect in which the testes have failed to descend into the pouchlike structure known as the scrotum (cryptorchidism); deficient activity of the testes (hypogonadism); and/or abnormal placement of the urinary opening (hypospadias), such as on the underside of the penis.
In many cases, Monosomy 8p is also characterized by various structural malformations of the heart that are present at birth (congenital heart defects). Such defects may include an abnormal opening in the wall (septum) that separates the two lower or the two upper heart chambers (ventricular or atrial septal defects) or where the wall between the atria joins the wall between the ventricles (atrioventricular septal defect), allowing some oxygen-rich blood to recirculate through the lungs and potentially leading to rising blood pressure in the lungs (pulmonary hypertension).
In some cases, additional cardiac defects may be present, such as underdevelopment (hypoplasia) of the right ventricle; abnormal narrowing (stenosis) of the opening between the pulmonary artery and the right ventricle (pulmonary stenosis); and/or other abnormalities. (The pulmonary artery carries oxygen-depleted blood from the right ventricle to the lungs, where the exchange of oxygen and carbon dioxide occurs. The aorta, the major artery of the body, arises from the left ventricle and supplies oxygen-rich blood to most arteries.)
In those with congenital heart defects, associated symptoms and findings may vary, depending on the size, nature, and/or combination of heart malformations present and other factors. Some individuals may show no apparent symptoms (asymptomatic). However, in other cases, symptoms and findings may include difficulties feeding, poor growth, difficult or labored breathing (dyspnea), profuse sweating, recurrent lung infections, an impaired ability of the heart to pump blood efficiently to the lungs and the rest of the body (heart failure), bluish discoloration of the skin and mucous membranes (cyanosis), enlargement of the heart, and/or other abnormalities. In severe cases, congenital heart disease may lead to potentially life-threatening complications.
In cases of Chromosome 8, Monosomy 8p, there is deletion (monosomy) of an end (distal) portion of the short arm (p) of chromosome 8. "Distal" indicates away or farthest from a particular point of reference, meaning the chromosome's centromere (described below).
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, the distal portion of the short arm of chromosome 8 (8p), sometimes referred to as "8p", includes bands 8p21 through 8p23; the end or "terminal" of 8p is known as "8pter".
In individuals with this chromosomal syndrome, the length and location of the monosomic region of 8p may vary, potentially affecting the range and severity of associated symptoms and findings. Reported cases have included deletions beginning within bands 8p21, 8p22, or 8p23 (breakpoint) that may extend to 8pter (i.e., terminal deletions) or may be interstitial. ("Interstitial" in this context means situated between, such as between other regions of a chromosome.) A few cases have also been reported in which certain, more "proximal" interstitial deletions of 8p may be associated with particular features characteristic of the syndrome. (Proximal, which is the opposite of the term distal, indicates closer to or nearest a particular point of reference [i.e., the centromere].)
Researchers have mapped a gene (known as "GATA4") to the short arm of chromosome 8 (8p23.1) that is thought to control expression of other genes involved in cardiac development. Evidence suggests that deficiency or disruption of GATA4 may contribute to certain congenital heart defects seen in some individuals with distal deletions of 8p involving 8p23.1. For example, in a study of patients with deletions of band 8p23.1, researchers demonstrated that affected individuals with associated heart defects had only one copy of the GATA4 gene, while another patient without known cardiac defects had both copies of the gene.
In most cases, Chromosome 8, Monosomy 8p appears to be caused by spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically). 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.
Rare cases have also been reported that appear to result from a "balanced translocation" in one of the parents. Translocations occur when portions 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.
Chromosomal analysis and genetic counseling are typically recommended for parents of an affected child to help confirm or exclude the presence of a balanced translocation or other chromosomal rearrangement involving chromosome 8 in one of the parents.
Chromosome 8, Monosomy 8p appears to affect males and females in relatively equal numbers. Since the disorder was originally described in 1973, over 20 cases have been reported in the medical literature.
Symptoms of the following disorders may be similar to those of Chromosome 8, Monosomy 8p. Comparisons may be useful for a differential diagnosis:
Velocardiofacial syndrome (VCFS) is a rare genetic disorder characterized by a spectrum of abnormalities that may vary from case to case. The disorder is most frequently characterized by distinctive craniofacial features, including incomplete closure of the roof of the mouth (cleft palate), narrow eyelid folds (palpebral fissures), a prominent nose, and jaw malformations; congenital heart defects, particularly ventricular septal defects; low tone of voluntary (skeletal) muscles (hypotonia) during infancy; and/or learning disabilities. Less common features may include mental retardation; short stature; temporarily low levels of calcium in the blood during the newborn period (neonatal hypocalcemia); unusually slender hands and fingers; and inguinal or umbilical hernia. In infants with an inguinal hernia, there is protrusion (herniation) of a portion of the intestine into the canal that passes through lower muscular layers of the abdominal wall. (In males, the inguinal canal is the tubular passageway through which the testes normally descend from the abdomen into the scrotum before birth.) An umbilical hernia is a skin-covered protrusion of intestine and the fold of fatty membrane in front of the intestine (omentum) through a defect in the abdominal wall at the navel (i.e., the umbilicus, where the umbilical cord joined the fetal abdomen). Occasional abnormalities associated with VCFS may include clouding of the lenses of the eyes (cataracts); abnormalities of blood vessels of the nerve-rich innermost membranes of the eyes (tortuous retinal vessels); underdevelopment or absence of the thymus; and/or other features. (The thymus, a lymphoid tissue organ, is thought to play a role in the body's immune response until puberty.) VCFS may appear to occur randomly for unknown reasons (sporadically) or may be familial, with autosomal dominant inheritance. The disorder often appears to result from deletion of part of the long arm of chromosome 22 (22q11). However, some cases have also been described in which chromosomal abnormalities other than monosomy 22q11 have been associated with features characteristic of VCFS; for example, in one case, a child with deletion of 8p23.1-pter had features similar to those seen in VCFS. (For further information on this disorder, choose "velocardiofacial" as your search term in the Rare Disease Database.)
Additional chromosomal disorders may be characterized by symptoms and findings similar to those associated with Chromosome 8, Monosomy 8p. 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.)
In some instances, the diagnosis of Chromosome 8, Monosomy 8p 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 characteristic findings that suggest a chromosomal disorder or other abnormalities. 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 Monosomy 8p2.
Chromosome 8, Monosomy 8p2 may be diagnosed and/or confirmed after birth (postnatally) by a thorough clinical evaluation, identification of characteristic physical findings, chromosomal analysis, and other specialized tests. A thorough cardiac evaluation may also be advised to detect any heart abnormalities that may be present. Such evaluation may include a thorough clinical examination; evaluation of heart and lung sounds with a stethoscope; x-ray studies; tests that record the electrical activities of heart muscle (electrocardiography [EKG]); a technique in which sound waves are directed toward the heart, enabling evaluation of cardiac motion and structure (echocardiogram); or other measures.
In turn, because congenital heart defects are commonly associated with Monosomy 8p, chromosomal analysis is suggested for all infants who are diagnosed with certain cardiac anomalies in association with facial malformations or an unusually small head (microcephaly) or both.
The treatment of Chromosome 8, Monosomy 8p is directed toward the specific symptoms that are apparent in each individual. Such disease management may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; heart specialists (cardiologists); physicians who diagnose and treat disorders of the skeleton, muscles, joints, and related tissues (orthopedists); and/or other health care professionals.
For affected individuals with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be required. In some cases, physicians may also recommend surgical repair or correction of certain craniofacial malformations, genital defects, and/or other malformations associated with the disorder. The specific surgical procedures performed will depend on the size, nature, severity, and combination of anatomical abnormalities, their associated symptoms, and other factors.
Early intervention services may also be important in ensuring that affected children reach their potential. Special services that may be beneficial include special remedial education, speech therapy, physical therapy, and/or other medical, social, and/or vocational services. Genetic counseling will also be of benefit for families of affected children. 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, congenital heart defects, etc.].)
(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at firstname.lastname@example.org.)
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FROM THE INTERNET
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Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 192430; 3/4/03. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?192430.
Report last updated: 2009/04/08 00:00:00 GMT+0