NORD is very grateful to Sheila Dobin, PhD, Section Chief, Cytogenetics, PhD Medical Geneticist, Medical Genetics, Baylor Scott & White Health-Scott and White Medical Center-Temple, Texas A&M University Health Science Center.
Trisomy 5p is a rare chromosomal disorder in which all or a portion of the short arm (p) of chromosome 5 (5p) appears three times (trisomy) rather than twice in cells of the body. Often the duplicated portion of 5p (trisomy) is due to a complex rearrangement involving other chromosomes. These individuals have a variable phenotype depending on which chromosome is involved, the size of the duplication and whether there is loss of material from the same or another chromosome.
Affected individuals may have an isolated duplication of 5p, a ring or supernumerary marker chromosome made up of only 5p material and the pericentric area of 5q, or when there is a derivative chromosome (unbalanced) from a translocation (switch of material between chromosomes) involving the short arm of chromosome 5 and the short arm of chromosomes 13,14,15,21,or 22) . These individuals have less variability since all of the material involved is from chromosome 5p. The variability is due solely to the size and location of the duplication. The individuals with only the duplication allow a better description of the symptoms (phenotype) and definition of a critical region for certain symptoms (cardiac abnormalities and seizures). Many affected infants and children have abnormalities that include low muscle tone (hypotonia); an unusually large head (macrocephaly) and additional abnormalities of the head and facial (craniofacial) area; large abdominal regions, long, slender fingers (arachnodactyly); delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor impairment); and intellectual disability. Some affected individuals may have heart defects and seizures. Not all individuals with trisomy 5p will have all of the symptoms of the disorder.
The symptoms and physical findings associated with trisomy 5p are variable and depend on the location and size of the duplicated segment. The information reported here is from case reports with duplications, markers, rings or translocations involving the short arm of chromosome 5 with the short arm of an acrocentric chromosome (13,14,15,21,or 22). Other findings may be present if there are monosomies (deletions) due to complex rearrangements or translocations involving other chromosomes and the short arm of chromosome 5p.
Infants with the disorder may have a normal birth weight or intrauterine growth retardation (IUGR). There may be extra fluid around the baby (polyhydramnios) during the pregnancy, early labor, or a decrease in the fluid in the stomach of the baby. The decrease in the fluid is believed to be due to swallowing tube abnormalities (esophageal atresia). Apgars at birth may be lower than the expected 9/10 and have been reported in the range of 5/6 most likely due to respiratory distress (trouble breathing) and low muscle tone (hypotonia). At birth the soft parts of the skull where the bones of the skull come together (fontanels) may be enlarged. Growth delays after birth (postnatal growth retardation) are common along with abnormally diminished muscle tone (hypotonia). The muscle tone may be mixed with some areas such as the neck and trunk showing low muscle tone (hypotonia) and other areas such as the lower limbs showing increased muscle tone or stiffness (hypertonia).
There are characteristic malformations of the head and facial (craniofacial) area. The head may be unusually large (macrocephaly) and has been described as long from front to back (dolichocephaly). There may also be a broad forehead. CT and MRI have shown that some individuals increased fluid in the ventricles of the brain (hydrocephalus). The eyes may be widely spaced (hypertelorism), have an upslant to them and the opening for the eye (palpebral fissure) may be small. There may also bevertical skin folds covering the eyes’ inner corners (epicanthal folds). The eyes may be small (microopthalmia) or they may be an abnormal deviation of one eye in relation to the other (strabismus). Partial absence of tissue from the colored portion of the eyes (coloboma), or protrusion of the eyes from the orbit (exophthalmos) has been reported. The eyebrows may be sparse and a depressed nasal bridge may be present, with a broad nasal tip and the nose itself may be short. Ears are often low-set and there may be fewer creases of the ear (simple helix) or the ear may have indented areas (crumpled helix). Hearing tends to be normal. There may be a high arched palate. The chin is set back (retrognathia) but in a few cases, in older individuals, the chin is prominent. There may be a large tongue (macroglossia). There may be flattening of the cheek area (midface hyperplasia). Individuals are noted to have a short neck. In some cases, additional physical abnormalities may also be present, such as narrowing of the larynx (laryngostenosis), which is the organ that connects the throat (pharynx) with the windpipe (trachea). Some of these physical findings have been noted to be similar to a condition known as Binder syndrome.
Infants with trisomy 5p may also have a narrow chest with a prominent or distended abdomen. Some affected infants may also have structural heart (cardiac) malformations that are present at birth (congenital heart defects), such as an abnormal opening in the fibrous partition (septum) that separates the upper chambers of the heart (atrial septal defects) and/ or an abnormal opening in the fibrous partition that separates the lower chambers of the heart called a VSD (ventral septal defects). Some individual have problems with the urine collecting system in the kidneys (pyelectasis). Hyodceles (swelling of the scrotum) and hernias have been reported. Several children have been reported with dry skin or eczema.
There are also characteristic abnormalities of the hands and feet. These may include abnormally long, slender fingers (arachnodactyly); short first toes; or deformities in which the feet are abnormally twisted out of position or shape (clubfeet). Shortened femurs have also been described in association with 5p duplication.
Some affected infants may have feeding difficulties and an increased susceptibility to repeated respiratory infections. The increase in respiratory infections is thought to be due to a molecule that helps protect the lining of the mouth and respiratory track from bacteria. The molecule is called IGA (immunoglobulin A) and although it is produced in normal amounts, the amount secreted is decreased. Reports exist of incoordination of swallowing which leads to aspiration which can lead to pneumonia and feeding difficulties. Deaths have been reported due to respiratory problems.
Trisomy 5p may also be associated with abnormal delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor impairment) and varying levels of intellectual disability, including autism spectrum disorders. Abnormal episodes of uncontrolled electrical activity in the brain (seizures) are frequently reported and the seizures may require multiple medications. Speech is often delayed and children may have echolalia (repetitive speech patterns- like the child is echoing things that they have heard at some time in their life.). There may be repetitive movements of the hands (stereotypic movements). Attention Deficit Disorder is very common. Increase weight gain and obesity is reported in older individuals. There is one individual reported with swelling (lymphedema) of the legs. It is uncertain whether the lymphedema was due to the obesity or is a separate finding.
In individuals with trisomy 5p, all or a portion of the short arm (p) of chromosome 5 (5p) 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 5 includes bands 5p10 (at the centromere or constriction of the chromosome) to 5p15, which is the end of the short arm or “terminal” band of 5p (also known as “5pter”).
The range and severity of associated symptoms and findings may depend on the length and location of the trisomic (duplicated) portion of the chromosome. Even very small duplication in the 5p region have been implicated in both physical and neurodevelopmental abnormalities. Characteristic physical features of the syndrome have been reported in individuals with complete duplications of 5p as well as those with various partial duplications and individuals who are mosaics. Mosaicism is when there are two cell populations with in the body. Some cells have the duplication while other cells do not. Comparison of the features and the overlapping areas, allows for the definition of a critical region for various phenotypic features. For the majority of the phenotypic features to be present, the duplication must include 5p10 to 5p13.1. The critical region for cardiac abnormalities and seizures is the duplication of 15p13.3. Most physical features are due to a duplication of the bands 5p13.0 to 5p13.3. The critical region for developmental delay and intellectual disability is thought to be the duplication of 5p14 to 5p15. Individuals who only have the duplication of 5p14 to 5p15 may not have any physical findings. Two boys have been reported with no intellectual disability with duplication from 5p15.1 to 5p15.3 near the terminus (which is toward the terminus but beyond the area for reported intellectual disability) yet others have had delay. Additionally, a microduplication in the region of 5p13.1 to 5p13.2 has been reported in an dysmorphic autistic child with poor self-care. The critical region for epilepsy appears to be a duplication of 5p13.2-5p13.3.
Based upon the data for critical area, the gene NIPBL has been reported as possibly being the candidate gene for the syndrome. Since some individuals do not have a duplication that is within this critical area, other genes may also be adding to the phenotypic features. Another gene that has been reported to be a possible candidate gene for the clinical features observed is GDNF.
In most cases, trisomy 5p appears to be caused by spontaneous (de novo) errors very early in embryonic development. 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.
In some cases, the duplication may result from a balanced chromosomal rearrangement in one of the parents and in rare cases the translocation is a new event in the child (de-novo translocation). Translocations occur when a portion of one chromosome breaks off and switches places with another chromosome piece that has broken off. This switch results in the shifting of genetic material. In the parent, if all of the material is present, it is balanced and thus is usually harmless to the carrier. Offspring produced from a parent with a balanced translocation may be balanced and thus have no phenotypic features since there is no duplication or be unbalanced. If the translocation involves the short arm of chromosomes 13, 14, 15, 21 or 22, there is loss of material, but that material will not contribute to the phenotype since it does not include genetic material with unique genes. Thus, individuals who have an unbalanced translocation with the derivative chromosomes 13, 14, 15, 21 or 22 have a phenotype that is due to purely the gain or duplication of the 5p material. If they inherit the derivative 5 they will have loss of 5p material rather than a gain of 5p material. If any other chromosome is involved with chromosome 5 in an unbalanced translocation, the individual will have extra and missing material. Depending on which chromosomes are inherited, a duplication of 5p may be present with missing chromosomal material from the other chromosome involved in the translocation. A translocation may be suspected in individuals who have had multiple miscarriages.
Rare cases have also been reported in which the parental chromosomal rearrangement has been an inversion. An inversion is characterized by breakage of a chromosome in two places and reunion of the segment in the reverse order. The piece of the chromosome furthest away from the centromere is located closer to the centromere and the piece of chromosome closest to the centromere is now farther away from the centromere. Again an inversion is balanced (all of the pieces of genetic material are present) in the parent; but can lead to either balanced or unbalanced offspring. The size of the inversion and its location often will determine the risk for unbalanced offspring.
Multiple cases have been due to small supernumerary marker chromosomes comprised of all or a majority of material from the short arm of chromosome 5. These are often ring chromosome caused by two breaks in the chromosome. The breaks are more susceptible to allowing the ends to combine, forming a ring. Individuals with ring chromosomes may be mosaics, since the rings are not stable. In the case of 5p duplication, where most of the material is derived from the short arm, the ring will include a very small area on the long arm that is near the centromere that does not contain genes with known clinical consequence. Thus these individuals will have features that are solely due to the duplication of the short arm of chromosome 5. If more of the long arm of chromosome 5 is involved, the individual will have a phenotype that is slightly different and will varied from the commonly observed phenotype of individuals with duplication of 5p material alone. In fact, there has been a suggestion that some of the long arm of chromosome 5 may provide a protective effect of 5p duplication and thus these individuals have milder phenotype.
In observed cases, trisomy 5p has appeared to affect females slightly more often than males and affects all ethnic groups. More than 40 cases have been described since the original description by Lejeune in 1964.
A blood chromosome (cytogenetic) study or a chromosomal microarray analysis is required to make the diagnosis.
In some cases, a diagnosis of a chromosomal abnormality may be suggested before birth (prenatally) by specialized tests such as ultrasound, amniocentesis, or chorionic villus sampling (CVS). During fetal ultrasonography performed at 16-18 weeks gestation, 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. Ultrasounds using 3D technology may further define the physical abnormalities; however, to make a specific diagnosis of a duplication of 5p either chromosomal analysis or chromosomal microarray is necessary. In such cases, an amniocentesis is offered to the parents. During an amniocentesis at 16-18 weeks gestation, a sample of fluid that surrounds the developing fetus is removed. The cells within the fluid are grown in culture. After enough cells have grown, the cells are collected and processed for cytogenetic or chromosomal microarray analysis. Parents are counseled regarding the risks of amniocentesis and then are asked if they consent to the procedure.
A chorionic villus sampling (CVS) may be performed earlier in pregnancy (11-12 weeks gestation). CVS involves the removal of tissue samples from a portion of the placenta. Cells from the tissue are grown and cytogenetic or chromosomal microarray analysis performed. This testing is offered if there is an indication of a chromosomal abnormality from a nuchal translucency (ultrasound that examines the extra skin around the neck of the baby) performed at 11-12 weeks gestation or if there has been a previous child born with an abnormality due to the parent having a balanced rearrangement. Nuchal translucency and CVS require early knowledge of a pregnancy. Risks of the procedure will be explained and then parents are asked if they consent to the procedure being performed.
The diagnosis of trisomy 5p may be made or confirmed after birth (postnatal) based upon a thorough clinical evaluation, detection of characteristic physical findings, and cytogenetic or chromosomal microarray analysis. Chromosomal microarray analysis can more accurately identify the breakpoints involved in a trisomy 5p and will detect unbalanced but not balanced rearrangements. With this knowledge, certain physical features may be suspected and monitored (e.g., congenital heart defects, seizure activity).
After finding a duplication of the 5p region either prenatally or postnatally, a parental chromosome study may be indicated. The parental chromosome results aid in determining the risk of future offspring having a similar type of abnormality. Genetic counseling is recommended for parents of an affected child to help confirm or exclude the presence of a balanced translocation or other chromosomal rearrangement involving chromosome 5 in one of the parents.
The treatment of trisomy 5p is directed toward the specific symptoms exhibited by the 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. A geneticist aids in determining what specialists are needed, coordinates the care of the affected individual, and provides genetic counseling regarding risks for future pregnancies and risks for other family members Other professionals may include pediatricians for general health assessment; surgeons; cardiologists; cardiac surgeons; ophthalmologists; ear, nose and throat specialists, neurologists and/or other health care professionals.
In some affected individuals, treatment may include surgical repair of certain craniofacial, 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 require an MRI or CT scan of the head to diagnose and possibly treat any excess fluid in the ventricles of the brain. There may be the need to place a gastric feeding tube (G-tube or button) to aid with feeding difficulties. Certain foods may need to be avoided. To treat seizures, multiple medications may be necessary. Treatment may also include measures to help prevent or aggressively treat respiratory infections. Other treatment is symptomatic and supportive.
Early intervention is important to ensure that children with trisomy 5p reach their potential. Special services are beneficial and include special education, social, and/or vocational services.
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: [email protected] For information about clinical trials sponsored by private sources, contact: www.centerwatch.com For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/ Contact for additional information about chromosome 5, trisomy 5p: Sheila Dobin, PhD Section Chief, Cytogenetics PhD Medical Geneticist/Clinical Cytogeneticist Baylor Scott and White Health Scott & White Medical Center-Temple Texas A&M University Health Science Center 2401 S 31st Street MS-1-043 Temple, Texas 76508 Phone: 254-724-3704 Fax: 244-724-6803 [email protected]
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