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Last updated:
4/10/2024
Years published: 1986, 1992, 1994, 2000, 2001, 2004, 2020, 2024
NORD gratefully acknowledges Anthony Smyth and Grace Seibert, NORD Editorial Interns from the University of Notre Dame, and Deborah A. Bruns, PhD, Professor, Special Education Program, School of Education, Southern Illinois University Carbondale, for assistance in the preparation of this report.
Trisomy 18 is a rare chromosomal disorder in which all or a critical region of chromosome 18 appears three times (trisomy) rather than twice in cells of the body. In some children, trisomy 18 may be present in only a percentage of cells, whereas other cells contain the typical chromosomal pair (mosaicism). Trisomy 18 is usually not inherited but occurs by chance.
Trisomy 18 may be a life-threatening condition; some affected children die before birth or within the first month of life. Some individuals have survived to their teenage years and beyond, with a range of medical and developmental needs. Research indicates that babies with trisomy 18 who had a heavier birthweight, longer gestation and are female may have fewer health problems. In addition, aggressive interventions such as surgery to correct heart defects can lengthen life.
Depending on the specific location of the duplicated (trisomic) portion of chromosome 18 and the percentage of cells, symptoms and findings can be extremely variable from person to person. Most affected infants have growth deficiency, feeding and breathing difficulties, and developmental delays. Individuals with trisomy 18 also have distinctive malformations of the head and facial (craniofacial) area as well as of the hands and feet, possible skeletal deformities, genitourinary issues and heart defects present at birth (congenital). Congenital heart defects and associated respiratory difficulties may lead to potentially life-threatening complications during infancy or childhood. Treatment is dependent upon the specific symptoms present, recommendations from the medical team and parent/family preference. In addition, guidelines for management are now available to assist in planning and decision making.
The symptoms associated with trisomy 18 are extremely variable. Severity can be dependent upon the percentage of cells that contain the third copy of the chromosome (mosaicism), but this percentage can change as a child grows as well as what type of sample was obtained (saliva versus blood for example). In many patients, there is decreased movement in utero. This may be due to polyhydramnios (excess amniotic fluid) during the mother’s pregnancy.
There are several common findings before birth (prenatally) and during infancy which are associated with trisomy 18. Affected infants are often small for gestational age and may have poor suckling ability and associated feeding difficulties that can be supported with tube feeding. There are also distinctive malformations of the head and facial (craniofacial) area. Many infants with trisomy 18 also have malformations of the hands and feet, additional skeletal defects, and structural abnormalities of the heart (congenital heart defects) and undescended testes in affected males (cryptorchidism).
Skeletal muscles and underlying connective and fatty tissues (subcutaneous and adipose tissue) may be underdeveloped (hypoplastic). Additional characteristics during infancy may include diminished muscle tone (hypotonia) followed by unusually increased tone (hypertonia) and muscle stiffness (rigidity) that is often due to tremors or seizures; a weak cry; decreased response to environmental sounds due to anatomical abnormities of the ear; and/or repeated episodes in which there is a temporary cessation of breathing due to central or obstructive apnea, which can be identified and treated in most children.
Many infants with trisomy 18 also have distinctive characteristics of the craniofacial region. These may include a small head (microcephaly) that appears unusually long and narrow (dolichocephaly); a prominent back region of the head (occiput); a small mouth (microstomia); incomplete closure of the roof of the mouth (cleft palate) – this is rare; , the palate may be narrow and/or an abnormal groove in the upper lip (cleft lip); a small jaw (micrognathia); or a short, webbed neck. Affected infants may also have an upturned nose; and low-set, posteriorly rotated ears and narrow ear canals. Monitoring by an audiologist is recommended.
Trisomy 18 may also be characterized by additional eye (ocular) malformations. There is often evidence of widely spaced eyes (ocular hypertelorism) with slanted or narrow eyelid folds (palpebral folds); and vertical skin folds covering the eyes’ inner corners (epicanthal folds). There may be drooping of the upper eyelids (ptosis) and an inability to completely close the eyes. Some affected infants also have clouding of the normally transparent front regions of the eyes (corneas); loss of transparency of the lenses (cataracts); or unusual smallness of the eyes (microphthalmia). Additional ocular malformations may include abnormal deviation of one eye in relation to the other (strabismus); inequality in the diameter of the pupils (anisocoria); rapid involuntary eye movements (nystagmus); and/or a decreased response to visual stimuli. Monitoring by an ophthalmologist is recommended.
Many infants with trisomy 18 also have characteristic malformations of the hands and feet. The hands are typically clenched, with overlapping of the index finger (second finger) over the third finger and the “pinky” (fifth finger) over the fourth. Frequent findings also include unusual skin ridge patterns (dermatoglyphics) on the fingers and palms; underdeveloped (hypoplastic) nails, particularly those of the fifth fingers and toes; and abnormal deviation of the great toes (hallux) in an upwardly bent position (dorsiflexion). In some children, additional features may be present such as extra fingers or toes (polydactyly); webbing (syndactyly) of one or more toes; or the feet appear shaped like the rocker of a rocking chair (“rocker-bottom feet”) with abnormal prominence of the heel bones (calcaneus). Some infants also have a foot deformity in which the heels are turned inward, and the soles are flexed or clubfeet (talipes equinovarus). Custom made orthotics and/or braces as well as stretching and specific exercises can assist with many of these malformations. Physical and occupational therapists as well as orthopedic specialists can provide recommendations.
Many infants with trisomy 18 also have skeletal malformations such as a short breastbone (sternum); a small pelvis with limited outward movements (abduction) of the hips; or abnormalities of the ribs. There may be defects of certain bones of the spinal column (vertebrae), including sideways curvature of the spine (scoliosis); underdevelopment of one half of certain vertebrae (hemivertebrae); or abnormal fusion of vertebrae. Depending on a child’s specific needs, orthotics and adaptive equipment may be prescribed to address movement concerns.
As mentioned above, in males with trisomy 18, the testes may fail to descend into the scrotum (cryptorchidism). Trisomy 18 may also be associated with additional genital malformations. In some affected males, there may be division of the scrotum into two parts (bifid scrotum) and/or abnormal placement of the urinary opening (hypospadias), such as on the underside of the penis. In some females with the disorder, there is underdevelopment (hypoplasia) of the outer skin folds (labia majora) surrounding the vaginal opening and abnormal prominence of the relatively small, sensitive protrusion (clitoris) that forms part of the female external genitalia.
Trisomy 18 is also often characterized by structural heart (cardiac) defects that are present at birth (congenital heart defects). Many affected infants have an abnormal opening in the fibrous partition (septum) that separates the lower chambers of the heart (ventricular septal defect; VSD). Another common finding is persistence of the fetal opening between the two major arteries (aorta, pulmonary artery) that emerge from the heart (patent ductus arteriosus; PDA). Additional heart defects may be present including narrowing (stenosis) of the opening between the right ventricle and the artery that carries oxygen-deficient blood to the lungs (pulmonary artery); narrowing of the major artery that transports oxygen-rich blood from the heart to all parts of the body (coarctation of the aorta); and/or abnormalities of heart valves. Monitoring by a pediatric cardiologist is necessary and should include discussion of palliative and intensive surgeries as appropriate. There is a growing willingness to perform surgery to correct heart defects in children with trisomy 18.
Some infants with trisomy 18 have malformations of the abdominal wall and the kidneys. For example, there may be protrusion of portions of the intestine through an abnormal opening in muscles of the groin (inguinal hernia) or the abdominal wall near the navel (umbilical hernia). Some infants with trisomy 18 have an omphalocele, a birth defect in which varying amounts of intestines or other abdominal organs (viscera), covered by a membrane-like sac, protrude through an opening in the abdominal wall near the navel. Some affected infants may have kidneys that are in an abnormal position (ectopic) or joined together (horseshoe kidneys) or contain multiple cysts (polycystic kidneys). There may also be swelling of the kidneys with urine due to narrowing or blockage of the tubes that carry urine from the kidneys to the bladder (hydronephrosis). Some children have a rare kidney cancer called Wilms tumor or liver cancer (hepatoblastoma) which can be treated. Scans every six months are advised.
Some affected infants may also have malformations of the brain and spinal cord (central nervous system; CNS). These may include absence (agenesis) or underdevelopment (hypoplasia) of the thick band of nerve fibers connecting the two hemispheres of the brain (corpus callosum); or protrusion of part of the spinal cord and its surrounding membranes (meninges) through an abnormal opening in the spinal column (myelomeningocele).
Trisomy 18 is also typically characterized by intellectual disability, along with delayed verbal and motor development. These children do communicate through facial expressions, gestures and vocalizations. Some can use augmentative communication devices and systems. Mobility needs can be addressed through orthotics, gait trainers and other assistive devices. Individuals with trisomy 18 recognize family members and caregivers and can display a range of emotions including indicating preferences for items and people in their environment.
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” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered.
In individuals with trisomy 18, all or a particular region of chromosome 18 is present three times (trisomy) rather than twice within cells. This extra genetic material from the third copy of the chromosome disrupts typical development and causes characteristic features of the condition. In about 5% of patients, only some cells in the body contain the extra 18th chromosome (mosaicism). Very rarely, an extra piece of chromosome 18 is attached to another chromosome (translocation trisomy 18 or partial trisomy 18). If only part of the long (q) arm of chromosome 18 is present in three copies, the symptoms may be less severe than in people with full trisomy 18.
Duplication of a specific region or regions of chromosome 18 is responsible for the symptoms and findings that characterize the condition. The severity and range of symptoms may depend on the length and location of the duplicated portion of the chromosome as well as the percentage of cells with the duplication. In individuals with partial trisomy of chromosome 18 who have characteristic symptoms of the disorder, evidence suggests that a critical region associated with trisomy 18 is duplication at band 18q11.
In most individuals with the disorder, duplication of chromosome 18 is caused by spontaneous (de novo) errors during the division of reproductive cells in one of the parents (e.g., nondisjunction during meiosis). Reports suggest that the risk of such errors may increase with advanced parental age. In cases in which only a percentage of cells contain three copies (mosaicism), errors may also occur during cellular division after fertilization (mitosis).
In some individuals, trisomy 18 may result from a translocation involving chromosome 18 and another chromosome. Translocations occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. Such translocations may occur spontaneously for unknown reasons (de novo) or be transmitted by a parent who is a carrier of a “balanced” translocation. (If a chromosomal rearrangement is balanced–i.e., consists of an altered but balanced set of chromosomes–it is usually harmless to the carrier. However, balanced translocations are sometimes associated with a higher risk of abnormal chromosomal development in the carrier’s offspring. Chromosomal testing may determine whether a parent has a balanced translocation.) A person with a balanced translocation had an increased risk with each pregnancy to have a child with trisomy 18.
Trisomy 18 affects females more frequently than males by a ratio of three or four to one. Large population surveys indicate that it occurs in about one in 5,000 to 7,000 livebirths. The frequency of trisomy 18 appears to increase with advancing maternal age. Reports indicate the mean maternal age is 32.5 years. There are also reports of mothers in their late teens and early 20’s.
A diagnosis of trisomy 18 may be suspected before birth based upon specialized testing such as fetal ultrasonography and maternal serum screening. During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing findings that may suggest a chromosomal disorder or other abnormalities. In addition, screening tests that reveal abnormal levels of certain “markers” in the mother’s blood may suggest an increased risk of trisomy 18 or other chromosomal abnormalities (e.g., Down syndrome). Such tests measure the levels of specific substances in the blood, including alpha-fetoprotein (AFP); human chorionic gonadotropin (hCG); unconjugated estriol; or other markers. If such screening studies reveal abnormal levels of these markers, additional testing may be recommended, such as amniocentesis or chorionic villus sampling (CVS) for chromosomal analysis. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed. CVS involves the removal of tissue samples from a portion of the placenta.
The diagnosis of trisomy 18 may also be confirmed after birth based on a thorough clinical evaluation, detection of characteristic physical findings, and chromosomal analysis. For infants diagnosed with trisomy 18, careful monitoring and specialized testing may be conducted to ensure early detection and appropriate management of conditions commonly associated with trisomy 18 such as cardiac defects and kidney concerns.
Treatment
The treatment of trisomy 18 is directed toward the specific symptoms in each affected individual. Treatment often requires the coordinated efforts of a multidisciplinary team of medical professionals.
For many affected infants, supportive measures may be required for the intake of necessary nutrients such as delivery of liquid nutrients to the stomach through a tube inserted through the nose (nasogastric tube feeding) or stomach (gastrostomy). Tube feeding may be short or long term and can be easily learned by parents and caregivers. In addition, oxygen therapy may be required to ensure sufficient oxygen saturation or placement of a tracheostomy. Some individuals need support from a ventilator after invasive procedures or surgeries and most can be successfully weaned. It is critical for the medical team, parents and caregivers to make decisions together based on each individual child’s needs.
Recommended treatment may include surgical interventions to help to improve quality of life and to extend life. The surgical procedures performed will depend upon the nature and severity of the condition such as a heart defect or correct scoliosis, their associated symptoms and other factors. In recent years, many individuals have had successful heart surgery to correct a VSD. This type of aggressive intervention is offered as well as palliative options depending on characteristics such as age, weight, response to anesthesia and parent and family preference.
Individuals with trisomy 18 may have a higher risk of developing certain cancers, so imaging and lab exams are recommended at specific intervals. For example, monitoring for Wilms tumor (a rare kidney cancer) is recommended every three months by abdominal ultrasound for children over one year of age. Nephroblastomata is commonly seen as a precursor to Wilms tumor. The possibility of hepatoblastoma (liver cancer) has also been reported in children with trisomy 18. Chemotherapy and surgery for patients with stable heart function can prolong life.
A team approach for children with this disorder may include early intervention (birth to age three services) special education, physical therapy, occupational therapy and speech therapy in addition to necessary medical specialists and in home nursing care. Social services such as counseling and respite care may be recommended. Developmental, educational and therapeutic care tailored to each individual should be provided with frequent review of use and progress with assistive equipment, adjustment of therapy minutes and educational goals as the child grows older.
This resource suggests a shared decision-making model to help families and physicians provide the most optimal patient care.
Genetic counseling is recommended for families with children with trisomy 18.
The Tracking Rare Incidence Syndromes (TRIS) project is designed to raise awareness and provide support for families and professionals involved in the care of children and adults with rare trisomy conditions. The TRIS project seeks to increase the knowledge base on rare trisomy conditions, and to make this information available to families and interested educational, medical and therapeutic professionals. For more information, contact:
Tracking Rare Incidence Syndromes (TRIS) project
Phone: (618) 453-6747
Email: tris@siu.edu
Website: http://tris.siu.edu/
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 website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
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/
JOURNAL ARTICLES
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Mehl JM, Gelfond J, Carey JC, Cody JD. Causes of death in individuals with trisomy 18 after the first year of life. Am J Med Genet A. 2024;194(2):279-287. doi:10.1002/ajmg.a.63436
Alzahrani S, et al. The effect of cardiac surgery in children with trisomy 13 And trisomy 18: a systematic review and meta-analysis. International Journal of Life Science and Pharma Research 2023: 13:1.
Benson J, Stewart C, Kenna MA, Shearer AE. Otolaryngologic manifestations of trisomy 13 and trisomy 18 in pediatric patients. Laryngoscope. 2023;133(6):1501-1506. doi:10.1002/lary.30350
Glinianaia SV, Rankin J, Tan J, et al. Ten-year survival of children with trisomy 13 or trisomy 18: a multi-registry European cohort study. Arch Dis Child. 2023;108(6):461-467. doi:10.1136/archdischild-2022-325068
Hafezi N, Jensen AR, Saenz ZM, et al. Surgical history and outcomes in trisomy 13 and 18: a thirty-year review. J Pediatr Surg. 2023;58(8):1512-1519. doi:10.1016/j.jpedsurg.2022.10.010
Jaspersen SL, Bruns DA, Candee MS, Battaglia A, Carey JC, Fishler KP. Seizures in trisomy 18: prevalence, description, and treatment. Am J Med Genet A. 2023;191(4):1026-1037. doi:10.1002/ajmg.a.63113
Koshida S, Takahashi K. Significant improvement in survival outcomes of trisomy 18 with neonatal intensive care compared to non-intensive care: a single-center study. PeerJ. 2023;11:e16537. Published 2023 Nov 29. doi:10.7717/peerj.16537
Shin BS, Jung MK and Shin SH. Neonatal treatment and outcomes of patients with trisomy 18 in the neonatal intensive Care unit: a single center study. Perinatology 2023; 34.2): 64-68.
Song IG, Shin SH, Cho YM, Lim Y. Survival of children with trisomy 18 associated with the presence of congenital heart disease and intervention in the Republic of Korea. BMC Pediatr. 2023;23(1):252. Published 2023 May 20. doi:10.1186/s12887-023-04056-4
Takai A, Yamagishi M, Ikeda K, et al. Effectiveness of cardiac palliative surgery for trisomy 18 patients with increased pulmonary blood flow. Am J Med Genet A. 2023;191(11):2703-2710. doi:10.1002/ajmg.a.63401
Cleary JP, Janvier A, Farlow B, Weaver M, Hammel J, Lantos J. Cardiac interventions for patients with trisomy 13 and trisomy 18: experience, ethical issues, communication, and the case for individualized family-centered care. World J Pediatr Congenit Heart Surg. 2022;13(1):72-76. doi:10.1177/21501351211044132
Cortezzo DE, Tolusso LK, Swarr DT. Perinatal outcomes of fetuses and infants diagnosed with trisomy 13 or trisomy 18. J Pediatr. 2022;247:116-123.e5. doi:10.1016/j.jpeds.2022.04.010
Silva C, Ferreira MC, Saraiva J, Cancelinha C. Trisomy 18-when the diagnosis is compatible with life. Eur J Pediatr. 2022;181(7):2809-2819. doi:10.1007/s00431-022-04477-w
Acharya K, Leuthner SR, Zaniletti I, et al. Medical and surgical interventions and outcomes for infants with trisomy 18 (T18) or trisomy 13 (T13) at children’s hospitals neonatal intensive care units (NICUs). J Perinatol. 2021;41(7):1745-1754. doi:10.1038/s41372-021-01111-9
Kepple JW, Fishler KP, Peeples ES. Surveillance guidelines for children with trisomy 18. Am J Med Genet A. 2021;185(4):1294-1303. doi:10.1002/ajmg.a.62097
Farmakis SG, Barnes AM, et al. Solid tumor screening recommendations in trisomy 18. Am J Med Genet. 2019;179A:455-466.
Janvier A, Farlow B, Barrington KJ, Bourque CJ, Brazg T, & Wilfond B. Building trust and improving communication with parents of children with Trisomy 13 and 18: A mixed-methods study. Palliative Medicine 2019; 0269216319860662.
Kato E, Kitase Y, Tachibana T, et al. Factors related to survival discharge in trisomy 18: A retrospective multicenter study. American Journal of Medical Genetics Part A. 2019; 179:1253–1259.
Taira R, Inoue H, Sawano T, et al. Management of apnea in infants with trisomy 18. Developmental Medicine & Child Neurology 2019: Nov 25. doi: 10.1111/dmcn.14403. [Epub ahead of print]
Alkhamdi MA, Diogo R, et al. Detailed Musculoskeletal Study of a Fetus with Trisomy-18 (Edwards Syndrome) with Langer’s Axillary Arch, and Comparison with Other Cases of Human Congenital Malformations. J Anat Sci Res. 2018;1:1-8.
Inuoe A, Suzuki R, et al. Therapeutic experience with hepatoblastoma associated with trisomy 18. Pediatr Blood Cancer. 2018;65:e27093.
Peterson R, Calamur N, Fiore A, Huddleston C, & Spence K. Factors influencing outcomes after cardiac intervention in infants with trisomy 13 and 18. Pediatric Cardiology 2018; 39(1): 140-147.
Kosiv KA, Gossett JM, Bai S, & Collins RT. Congenital heart surgery on in-hospital mortality in trisomy 13 and 18. Pediatrics 2017; 140(5): e20170772.
Patterson F. Taylor G, et al. Transitions in Care for Infants with Trisomy 13 or 18. Amer J Perinatol. 2017;34:887-894.
Peterson JK, Kochilas LK, Catton KG, Moller JH, & Setty SP. Long-term outcomes of children with trisomy 13 and 18 after congenital heart disease interventions. The Annals of Thoracic Surgery 2017; 103(6): 1941-1949.
Andrews SE, Downey AG, et al. Shared decision making and the pathways approach in the prenatal and postnatal management of the trisomy 13 and trisomy 18 syndromes. Am J Med Genet C Semin Med Genet. 2016;172:257-263.
Bruns DA, & Martinez A. An analysis of cardiac defects and surgical interventions in 84 cases with full trisomy 18. American journal of medical genetics Part A 2016; 170(2): 337-343.
Carey JC, & Barnes AM. Wilms tumor and trisomy 18: Is there an association? In American Journal of Medical Genetics Part C: Seminars in Medical Genetics 2016; 172(3): 307-308.
Donovan JH, Krigbaum G & Bruns DA.Medical interventions and survival by gender of children with trisomy 18. In American Journal of Medical Genetics Part C, Seminars in Medical Genetics 2016;172(3): 272-278.
Josephsen JB, Armbrecht ES, Braddock SR, & Cibulskis CC. Procedures in the 1st year of life for children with trisomy 13 and trisomy 18, a 25‐year, single‐center review. In American Journal of Medical Genetics Part C: Seminars in Medical Genetics 2016;. 172(3):264-271.
Meyer RE, Liu G, Gilboa SM, et al & National Birth Defects Prevention Network. Survival of children with trisomy 13 and trisomy 18: a multi‐state population‐based study. American journal of medical genetics Part A 2016; 170(4): 825-837.
Nelson KE, Rosella LC, et al. Survival and surgical interventions for children with trisomy 13 and 18. JAMA. 2016;316:420-428.
Satgé D, Nishi M, Sirvent N, & Vekemans M. A tumor profile in Edwards syndrome (trisomy 18). In American Journal of Medical Genetics Part C: Seminars in Medical Genetics 2016;172(3): 296-306.
Bruns DA. Developmental status of 22 children with trisomy 18 and eight children with trisomy 13: implications and recommendations. American Journal of Medical Genetics Part A 2015; 167(8):1807-1815.
Cereda A & Carey JC. The trisomy 18 syndrome. Orphanet Journal of Rare Diseases 2012; 7(1): 81.
Palomaki GE, Deciu C, et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med. 2012;14:296–305.
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/