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 4, Partial Trisomy Distal 4q is a rare chromosomal disorder in which a portion of the fourth chromosome appears three times (trisomy) rather than twice in cells of the body. Associated symptoms and findings may vary from case to case. However, common features include growth deficiency; mental retardation; distinctive malformations of the skull and facial (craniofacial) region, including an unusually small head (microcephaly), malformed ears, and a prominent nasal bridge; and/or defects of the hands and feet. In some cases, additional physical abnormalities may also be present, such as structural defects of the heart that are present at birth (congenital heart defects); genital abnormalities in affected males; urinary tract defects; and/or other findings. In most cases, the trisomy appears to result from a balanced chromosomal rearrangement in one of the parents; rarely, it is thought to arise from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically).
Chromosome 4, Partial Trisomy Distal 4q is commonly characterized by a low birth weight and growth deficiency. In addition, many affected infants have low muscle tone (hypotonia), with unusual “floppiness” of voluntary (skeletal) muscles, or excessive muscle tone (hypertonia), with increased resistance to passive stretching. Additional characteristic features include mental retardation and delays in the acquisition of skills that require the coordination of mental and motor activities (psychomotor retardation).
Partial Trisomy Distal 4q is also associated with various malformations of the skull and facial (craniofacial) region. Such features commonly include an abnormally small head (microcephaly); a narrow, sloping forehead; relatively large, low-set, malformed (dysplastic) ears; and/or a short neck. Affected individuals may also have a prominent nasal bridge; an abnormally short vertical groove in the center of the upper lip (i.e., short philtrum); downturned corners of the mouth; pursed lips; a pointed chin; and/or a small, receding jaw (microretrognathia). Various eye (ocular) abnormalities may also be present, such as widely spaced eyes (ocular hypertelorism); narrow, downslanting eyelid folds (palpebral fissures); vertical skin folds that may cover the eyes’ inner corners (epicanthal folds); and/or abnormal deviation of one eye in relation to the other (strabismus). Additional ocular abnormalities have also been reported, including drooping of the upper eyelids (ptosis) and/or unusually small eyes (microphthalmia).
Limb defects are also commonly associated with the syndrome. Such abnormalities may include malformed hands and feet; abnormal development of the thumbs; webbing or fusion (syndactyly) of certain toes; and/or a deformity in which the heel is turned outward from the midline of the leg (talipes valgus).
In some cases, additional physical features may be present. Male infants typically have a developmental defect in which the testes have failed to descend into the pouchlike structure known as the scrotum (cryptorchidism). In addition, about 30 percent of affected infants may have an inguinal or umbilical hernia. In those with an inguinal hernia, there is protrusion (i.e., 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).
Approximately half of affected infants also have various abnormalities of the kidneys and urinary tract, such as underdevelopment of the kidneys (renal hypoplasia); abnormal union of the two kidneys at the base, forming a “horseshoe” shape (horseshoe kidney); swelling (distension) of the kidneys with urine (hydronephrosis) due to narrowing or blockage of the tubes (i.e., ureters) that carry urine from the kidneys into the bladder; and/or other abnormalities. In addition, about half of those with the syndrome also have heart (cardiac) defects and blood vessel (vascular) abnormalities. According to reports in the medical literature, severe cardiac and/or renal defects may lead to potentially life-threatening complications in some cases.
In individuals with Chromosome 4, Partial Trisomy Distal 4q, an end (distal) region of the long arm (q) of the fourth chromosome appears three times (trisomy) rather than twice in cells of the body. “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 long arm of chromosome 4 includes bands 4q11-q13, bands 4q21-q28, and bands 4q31-q35; the end or “terminal” of 4q is known as “4qter.” In addition, the region containing bands 4q21-q28 is sometimes referred to as “4q2,” while that containing bands 4q31-q35 is also called “4q3.”
In individuals with this chromosomal syndrome, the length of the trisomic (duplicated) region of distal 4q may vary: reported cases have included trisomies ranging from 4q21-qter to 4q32-qter. According to investigators, the severity of associated symptoms and findings does not appear to directly correlate with the length of the trisomy. In addition, some affected individuals may have potentially undetectable duplications or deletions (monosomies) of another chromosome (e.g., due to a parental translocation [see below]), possibly contributing to variability of associated clinical features.
In most reported cases, Chromosome 4, Partial Trisomy Distal 4q is due to 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.
Rare cases have also been reported that appear to result from spontaneous (de novo) errors very early in embryonic development. In such de novo cases, the parents of the affected child usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality.
Chromosomal analysis and genetic counseling are typically recommended for the parents of an affected child to help confirm or exclude the presence of a balanced translocation or other chromosomal rearrangement involving chromosome 4 in one of the parents.
In observed cases, Chromosome 4, Partial Trisomy Distal 4q has appeared to affect males and females in relatively equal numbers. More than 60 cases have been reported in the medical literature.
In some cases, the diagnosis of Chromosome 4, Partial Trisomy Distal 4q may be suggested before birth (prenatally) by specialized tests such as ultrasound, amniocentesis, percutaneous umbilical blood sampling, 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. Fetal blood samples may be obtained with a needle guided via ultrasound into a blood vessel in the umbilical cord. Chromosomal analysis performed on such fluid or tissue samples may reveal the presence of Partial Trisomy Distal 4q.
Chromosome 4, Partial Trisomy Distal 4q may be diagnosed and/or confirmed after birth (postnatally) by a thorough clinical evaluation, identification of characteristic physical findings, and chromosomal analysis. In addition, diagnostic evaluation may include various studies to help detect and/or characterize certain abnormalities that may be associated with the disorder (e.g., particular craniofacial defects, other skeletal malformations, renal defects, etc.). In addition, a thorough cardiac evaluation may 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 through use of a stethoscope, and specialized tests that enable physicians to evaluate the structure and function of the heart (e.g., x-ray studies, electrocardiography [EKG]), echocardiography).
The treatment of Chromosome 4, Partial Trisomy Distal 4q is directed toward the specific symptoms and findings that are apparent in each individual. Such disease management may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; physicians who diagnose and treat disorders of the skeleton, muscles, joints, and related tissues (orthopedists); heart specialists (cardiologists); urinary tract and kidney specialists; 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 addition, in some cases, physicians may recommend surgical repair or correction of certain craniofacial malformations, additional skeletal abnormalities, genital defects, hernias, renal and urinary tract anomalies, and/or other malformations associated with the disorder. The specific surgical procedures performed will depend upon the nature and severity of the 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, 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.].)
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