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, Trisomy 4p is a rare chromosomal disorder in which all or a portion of the short arm (p) of chromosome 4 appears three times (trisomy) rather than twice in cells of the body. Associated symptoms and physical findings may vary greatly in range and severity from case to case. Such variability may depend upon the specific length and location of the duplicated (trisomic) portion of chromosome 4p as well as other factors. However, many affected infants may have feeding and breathing difficulties, characteristic malformations of the head and facial (craniofacial) area, and abnormalities of the hands and feet. Additional features may include other skeletal defects, genital abnormalities in affected males, or heart (cardiac) defects. Trisomy 4p is also characterized by severe mental retardation.
The symptoms and physical findings associated with Chromosome 4, Trisomy 4p may be variable. However, in many cases, the disorder is characterized by growth deficiency before and after birth (prenatal and postnatal growth retardation); feeding problems during early infancy; and increased muscle tone (hypertonia) in the first months of life, followed by diminished muscle tone (hypotonia). Affected infants may also have respiratory difficulties, potentially leading to life-threatening complications.
Many infants with Trisomy 4p also have characteristic malformations of the head and facial (craniofacial) area. These may include an abnormally small head (microcephaly); a relatively small, flat forehead; a flat or depressed nasal bridge with a “bulb-shaped” (bulbous) nasal tip; and large, malformed (dysplastic) ears. Affected infants may also have widely spaced eyes (ocular hypertelorism) with abnormal prominence of the ridges above the eyes (supraorbital ridges). Additional craniofacial abnormalities may be present, such as a prominent chin, a relatively large tongue (macroglossia), irregularities of the teeth, and a short neck.
Trisomy 4p may also be characterized by abnormalities of the hands and feet. For example, there may be inward deviation or bending (clinodactyly) of the fifth fingers (“pinkies”); permanent flexion of one or more fingers (camptodactyly); or malformations of the feet (e.g., “rocker-bottom” feet) with abnormal prominence of the heels. Some affected infants may also have unusually long, slender fingers or toes (arachnodactyly) or underdeveloped (hypoplastic) fingernails and toenails.
Additional skeletal malformations may be associated with Trisomy 4p. These may include dislocation of the hip; abnormal front-to-back and sideways curvature of the spine (kyphoscoliosis); malformation of certain bones of the spinal column (vertebrae); or absence of certain ribs or the presence of additional ribs. In addition, certain joints may become permanently flexed or extended in various fixed postures (joint contractures), resulting in limited movements.
Some individuals with Trisomy 4p may also have additional physical abnormalities. For example, affected males may have an unusually small penis (micropenis), abnormal placement of the urinary opening on the underside of the penis (hypospadias), or undescended testes (cryptorchidism). In some cases, additional abnormalities may include protrusion of portions of the intestine into muscles of the groin (inguinal hernia); structural abnormalities of the heart at birth (congenital heart defects); kidney (renal) malformations; or absence of the band of nerve fibers that joins the two hemispheres of the brain (agenesis of the corpus callosum). Some affected individuals may also develop episodes of uncontrolled electrical activity in the brain (seizures). In some cases, eye (ocular) abnormalities may also be present, such as abnormal smallness of the eyes (microphthalmia) or absence or defects of ocular tissue (colobomata) involving the middle region of the eyes (uvea).
Trisomy 4p is also typically characterized by severe mental retardation. Affected infants and children have delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation). In addition, many may have poor language development or lack the ability to speak.
In individuals with Chromosome 4, Trisomy 4p, all or a portion of the short arm (p) of chromosome 4 appears three times (trisomy) rather than twice in cells of the body. 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 short arm of chromosome 4 includes bands 4p11 to 4p16; the latter, which is the end or “terminal” band of 4p, is also known as “4pter”.
The range and severity of associated symptoms and findings may depend on the size and location of the trisomic (duplicated) portion of chromosome 4p. For example, evidence suggests that characteristic features of the syndrome are most likely due to duplication of bands 4p15.2 to 4p16.1. In addition, some individuals with Trisomy 4p may have potentially undetectable duplications or deletions (monosomies) of another chromosome (e.g., due to a balanced parental translocation [see below]), possibly contributing to the variability of associated clinical features.
In many cases, Chromosome 4, Trisomy 4p is due to a balanced chromosomal rearrangement in one of the parents. In most instances, the parental rearrangement is a “balanced translocation.” 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.
A few cases have also been reported in which the parental chromosomal rearrangement has been a pericentric inversion. A pericentric inversion is characterized by breakage of a chromosome in two places on either side of the centromere and reunion of the segment in the reverse order.
In other affected individuals, duplication of chromosome 4p has appeared to be caused by spontaneous (de novo) errors during early embryonic development that occur for unknown reasons (sporadically). The parents of a child with a “de novo” duplication 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 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.
Chromosome 4, Trisomy 4p appears to affect males and females in relatively equal numbers. Trisomy for the short arm of chromosome 4 was originally described in 1970 (Wilson MG) and delineated as a distinct clinical syndrome in 1977 (Gonzalez CH). More than 85 patients with the syndrome have been reported in the medical literature.
In some cases, a diagnosis of Trisomy 4p may be suggested before birth (prenatally) by specialized tests such as ultrasound, amniocentesis, or chorionic villus sampling (CVS). During fetal ultrasonography, reflected sound waves are used to create an image of the developing fetus. Ultrasound studies may reveal characteristic findings that suggest a chromosomal disorder or other developmental abnormalities in the fetus. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, whereas CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal analysis performed on the fluid or tissue samples may reveal the presence of Trisomy 4p.
The diagnosis of Trisomy 4p may be confirmed after birth (postnatally) based upon a thorough clinical evaluation, detection of characteristic physical findings, and chromosomal analysis. In addition, specialized testing may also be conducted to detect or characterize certain abnormalities that may be associated with the disorder. Such testing may include specialized imaging techniques, such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI); electroencephalography (EEG); or other specialized tests. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves form detailed cross-sectional images of certain organs and tissues. EEG is a noninvasive diagnostic technique that records the brain's electrical impulses. EEG studies may reveal brain wave patterns that may be suggestive of certain types of seizures.
In addition, congenital heart defects that may be associated with Trisomy 4p may be detected with specialized tests that enable physicians to evaluate the structure and function of the heart. Cardiac evaluation may include clinical examination with a stethoscope to evaluate heart and lung sounds; x-ray studies; tests that record the electrical activities of the heart muscle (electrocardiography [EKG]); a technique in which sound waves are directed toward the heart, enabling evaluation of cardiac motion and function (echocardiogram); or other measures (e.g., cardiac catheterization).
The treatment of Chromosome 4, Trisomy 4p is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals who may need to systematically and comprehensively plan an affected child's treatment. These professionals may include pediatricians; surgeons; specialists who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in neurological disorders (neurologists); physicians who diagnose and treat heart abnormalities (cardiologists); and/or other health care professionals.
In some affected individuals, treatment may include surgical repair of certain craniofacial, skeletal, genital, cardiac, or other abnormalities potentially associated with the disorder. The surgical procedures performed will depend upon the severity of the anatomical abnormalities, their associated symptoms, and other factors. Treatment may also include measures to help prevent or aggressively treat respiratory complications that may be associated with the disorder. Other treatment is symptomatic and supportive.
Early intervention may be important in ensuring that children with Chromosome 4, Trisomy 4p reach their potential. Special services that may be beneficial include special education, physical therapy, and/or other medical, social, and/or vocational services. Genetic counseling will also be of benefit for individuals with Trisomy 4p and their families.
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