eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Trisomy 18

Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, Pathology, Director of Perinatal Genetics and Genetic Laboratory Services, Louisiana State University Medical Center; Laboratory Director, Hema-Con Cancer Cytogenetics Laboratory, Gainesville, Florida
Contributor Information and Disclosures

Updated: Aug 8, 2007

Introduction

Background

Trisomy 18 was independently described by Edwards et al and Smith et al in 1960.1,2 Among liveborn children, trisomy 18 is the second most common autosomal trisomy after trisomy 21. The disorder is characterized by severe psychomotor and growth retardation, microcephaly, microphthalmia, malformed ears, micrognathia or retrognathia, microstomia, distinctively clenched fingers, and other congenital malformations.

Pathophysiology

Trisomy 18 severely affects all organ systems. In translocations that result in partial trisomy or in cases of mosaic trisomy 18, clinical expression is less severe, and survival is usually longer.

Frequency

United States

Prevalence is approximately 1 in 6000-8000 live births.

Mortality/Morbidity

  • Approximately 95% of conceptuses with trisomy 18 die as embryos or fetuses; 5-10% of affected children survive beyond the first year of life.
  • The high mortality rate is usually due to the presence of cardiac and renal malformations, feeding difficulties, sepsis, and apnea caused by CNS defects.
  • Severe psychomotor and growth retardation are invariably present in those who survive beyond infancy.

Race

Trisomy 18 has no racial predilection.

Sex

Approximately 80% of cases occur in females. The preponderance of females with trisomy 18 among liveborn infants (sex ratio 0.63) compared with fetuses with prenatal diagnoses (sex ratio 0.90) indicates a prenatal selection against males with trisomy 18 after the time of amniocentesis.

Age

Trisomy 18 is detectable during the prenatal and newborn periods.

Clinical

History

  • Prenatal history
    • Maternal polyhydramnios possibly related to defective sucking and swallowing reflexes in utero
    • Oligohydramnios secondary to renal defects
    • Disproportionately small placenta
    • Single umbilical artery
    • Intrauterine growth retardation
    • Weak fetal activity
    • Fetal distress
  • Clinical history
    • Apneic episodes
    • Poor feeding
    • Marked failure to thrive

Physical

  • Neurological
    • Delayed psychomotor development and mental retardation (100%)
    • Neonatal hypotonia followed by hypertonia, jitteriness, apnea, and seizures

    • Malformations (eg, microcephaly, cerebellar hypoplasia, meningoencephalocele, anencephaly, hydrocephaly, holoprosencephaly, Arnold-Chiari malformation, hypoplasia or aplasia of the corpus callosum, defective falx cerebri, frontal lobe defect, migration defect, arachnoid cyst, myelomeningocele)
  • Cranial - Microcephaly, elongated skull, narrow bifrontal diameter, wide fontanels, and prominent occiput
  • Facial - Microphthalmia, ocular hypertelorism, epicanthal folds, short palpebral fissures, iris coloboma, cataract, corneal clouding, abnormal retinal pigmentation, short nose with upturned nares, choanal atresia, micrognathia or retrognathia, microstomia, narrow palatal arch, infrequent cleft lip and cleft palate, preauricular tags and low-set, and malformed ears (faunlike with flat pinnae and a pointed upper helix)
  • Skeletal - Severe growth retardation, characteristic hand posture (ie, clenched hands with the index finger overriding the middle finger and the fifth finger overriding the fourth finger), camptodactyly, radial hypoplasia or aplasia, thumb aplasia, syndactyly of the second and third digits, arthrogryposis, rocker-bottom feet with prominent calcanei, talipes equinovarus, hypoplastic nails, dorsiflexed great toes, short neck with excessive skin folds, short sternum, narrow pelvis, and limited hip abduction
  • Cardiac
    • More than 90% of infants with trisomy 18 have cardiac malformations.

    • The most common abnormalities are ventricular septal defects with polyvalvular heart disease (pulmonary and aortic valve defects).
    • Other cardiac malformations include atrial septal defects, patent ductus arteriosus, overriding aorta, coarctation of aorta, hypoplastic left heart syndrome, tetralogy of Fallot, and transposition of great arteries.
  • Pulmonary - Pulmonary hypoplasia and abnormal lobation of the lung
  • Gastrointestinal - Omphalocele, malrotation of the intestine, ileal atresia, common mesentery, Meckel diverticulum, esophageal atresia with or without tracheoesophageal fistula, diaphragmatic eventration, prune belly anomaly, diastasis recti, absent gallbladder, absent appendix, accessory spleens, exstrophy of Cloaca, pyloric stenosis, imperforate or malpositioned anus, pilonidal sinus, and hernias (ie, umbilical, inguinal, diaphragmatic)
  • Genitourinary
    • Micromulticystic kidneys, double ureters, megaloureters, hydroureters, hydronephrosis, horseshoe kidneys, and unilateral renal agenesis

    • Cryptorchidism, hypospadias, and micropenis in males

    • Hypoplasia of labia and ovaries, bifid uterus, hypoplastic ovaries, and clitoral hypertrophy in females
  • Endocrine - Thymic hypoplasia, thyroid hypoplasia, and adrenal hypoplasia
  • Dermal (ie, dermatoglyphics) - Increased number of simple arches on the fingertips, transverse palmar crease, increased atd angle, and clinodactyly of the fifth fingers with a single flexion crease

Causes

  • Full trisomy 18 is responsible for 95% of Edwards syndrome cases. Mosaicism and translocations cause few cases. An extra chromosome 18 is responsible for the phenotype.
  • The incidence rate increases with advanced maternal age. In approximately 90% of cases, the extra chromosome is maternal in origin, with meiosis II errors occurring twice as frequently as meiosis I errors. This is in contrast to other human trisomies, which exhibit a higher frequency of nondisjunction in maternal meiosis I. Among cases resulting from paternal nondisjunction, most are the result of postzygotic mitotic errors.
  • Although full trisomy results from meiotic nondisjunction, mosaic trisomy is due to postzygotic mitotic nondisjunction. Mosaic trisomy 18 occurs when both a trisomy 18 cell line and a normal cell line are present in the same individual. Mosaic trisomy 18 accounts for approximately 5% of trisomy 18 cases. The clinical phenotype varies depending on the level of mosaicism and the tissue involved and ranges from the complete trisomy 18 phenotype to no dysmorphic features and normal intelligence.
  • Translocation trisomy gives rise to partial trisomy 18 syndrome. Partial trisomy 18 occurs when a segment of chromosome 18 is present in triplicate, often resulting from a balanced translocation carried by one parent. It accounts for approximately 2% of trisomy 18 cases.
  • The smallest extra region necessary for expression of serious anomalies of trisomy 18 appears to be 18q11-12.

More on Trisomy 18

Overview: Trisomy 18
Differential Diagnoses & Workup: Trisomy 18
Treatment & Medication: Trisomy 18
Follow-up: Trisomy 18
Multimedia: Trisomy 18
References
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References

  1. Edwards JH, Harnden DG, Cameron AH, et al. A new trisomic syndrome. Lancet. Apr 9 1960;1:787-90. [Medline].

  2. Smith DW, Patau K, Therman E, Inhorn SL. A new autosomal trisomy syndrome: multiple congenital anomalies caused by anextra chromosome. J Pediatr. Sep 1960;57:338-45. [Medline].

  3. Baty BJ, Blackburn BL, Carey JC. Natural history of trisomy 18 and trisomy 13: I. Growth, physical assessment, medical histories, survival, and recurrence risk. Am J Med Genet. Jan 15 1994;49(2):175-88. [Medline].

  4. Baty BJ, Jorde LB, Blackburn BL, Carey JC. Natural history of trisomy 18 and trisomy 13: II. Psychomotor development. Am J Med Genet. Jan 15 1994;49(2):189-94. [Medline].

  5. Bersu ET, Ramirez-Castro JL. Anatomical analysis of the developmental effects of aneuploidy in man-- the 18-trisomy syndrome: I. Anomalies of the head and neck. Am J Med Genet. 1977;1(2):173-93. [Medline].

  6. Bettio D, Levi Setti P, Bianchi P, Grazioli V. Trisomy 18 mosaicism in a woman with normal intelligence. Am J Med Genet A. Jul 15 2003;120(2):303-4. [Medline].

  7. Biagiotti R, Cariati E, Brizzi L, et al. Maternal serum screening for trisomy 18 in the first trimester of pregnancy. Prenat Diagn. Sep 1998;18(9):907-13. [Medline].

  8. Bronsteen R, Lee W, Vettraino IM, et al. Second-trimester sonography and trisomy 18. J Ultrasound Med. Feb 2004;23(2):233-40. [Medline].

  9. Carey JC. Trsiomy 18 and trisomy 13 syndromes. In: Cassidy SB, Allanson JE. Management of Genetic Syndromes. 2nd. New York: Wiley-Liss; 2005:555-68.

  10. Collins AL, Fisher J, Crolla JA, Cockwell AE. Further case of trisomy 18 mosaicism with a mild phenotype [letter]. Am J Med Genet. Mar 13 1995;56(1):121-2. [Medline].

  11. Embleton ND, Wyllie JP, Wright MJ, et al. Natural history of trisomy 18. Arch Dis Child Fetal Neonatal Ed. Jul 1996;75(1):F38-41. [Medline].

  12. Findlay I, Toth T, Matthews P, et al. Rapid trisomy diagnosis (21, 18, and 13) using fluorescent PCR and short tandem repeats: applications for prenatal diagnosis and preimplantation genetic diagnosis. J Assist Reprod Genet. May 1998;15(5):266-75. [Medline].

  13. Gilbert-Barnes E. Chromosome abnormalities. In: Gilbert-Barnes E, ed. Potter's Pathology of the Fetus and Infant. Vol 1. St Louis, Mo: Mosby; 1997:402-4.

  14. Gross SJ, Bombard AT. Screening for the aneuploid fetus. Obstet Gynecol Clin North Am. Sep 1998;25(3):573-95. [Medline].

  15. Hecht F, Bryant JS, Motulsky AG, Giblett ER. The no. 17-18 (E) trisomy syndrome. Studies on cytogenetics, dermatologlyphics, paternal age, and linkage. J Pediatr. Oct 1963;63:605-21. [Medline].

  16. Huether CA, Martin RL, Stoppelman SM, et al. Sex ratios in fetuses and liveborn infants with autosomal aneuploidy. Am J Med Genet. Jun 14 1996;63(3):492-500. [Medline].

  17. Kinoshita M, Nakamura Y, Nakano R, et al. Thirty-one autopsy cases of trisomy 18: clinical features and pathological findings. Pediatr Pathol. 1989;9(4):445-57. [Medline].

  18. Kjaer I, Keeling JW, Hansen BF. Pattern of malformations in the axial skeleton in human trisomy 18 fetuses. Am J Med Genet. Nov 11 1996;65(4):332-6. [Medline].

  19. Leporrier N, Herrou M, Herlicoviez M, Leymarie P. The usefulness of hCG and unconjugated oestriol in prenatal diagnosis of trisomy 18. Br J Obstet Gynaecol. Apr 1996;103(4):335-8. [Medline].

  20. Moyano D, Huggon IC, Allan LD. Fetal echocardiography in trisomy 18. Arch Dis Child Fetal Neonatal Ed. Nov 2005;90(6):F520-2. [Medline].

  21. Nicolaidis P, Petersen MB. Origin and mechanisms of non-disjunction in human autosomal trisomies. Hum Reprod. Feb 1998;13(2):313-9. [Medline]. [Full Text].

  22. Ramirez-Castro JL, Bersu ET. Anatomical analysis of the developmental effects of aneuploidy in man-- the 18-trisomy syndrome: II. Anomalies of the upper and lower limbs. Am J Med Genet. 1978;2(3):285-306. [Medline].

  23. Root S, Carey JC. Survival in trisomy 18. Am J Med Genet. Jan 15 1994;49(2):170-4. [Medline].

  24. Shields LE, Carpenter LA, Smith KM, Nghiem HV. Ultrasonographic diagnosis of trisomy 18: is it practical in the early second trimester?. J Ultrasound Med. May 1998;17(5):327-31. [Medline].

  25. Taylor AI. Autosomal trisomy syndromes: a detailed study of 27 cases of Edwards' syndrome and 27 cases of Patau's syndrome. J Med Genet. Sep 1968;5(3):227-52. [Medline].

  26. Tucker ME, Garringer HJ, Weaver DD. Phenotypic spectrum of mosaic trisomy 18: two new patients, a literature review, and counseling issues. Am J Med Genet A. Mar 1 2007;143(5):505-17. [Medline].

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Further Reading

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Keywords

Edwards syndrome, Edwards' syndrome, trisomy 18 syndrome, trisomy E syndrome, severe psychomotor retardation, severe growth retardation, microcephaly, microphthalmia, malformed ears, micrognathia, retrognathia, microstomia, clenched fingers, congenital malformations, cardiac malformations, renal malformations, polyhydramnios, oligohydramnios, small placenta, single umbilical artery, intrauterine growth retardation, weak fetal activity, fetal distress, delayed psychomotor development, mental retardation, neonatal hypotonia, cerebellar hypoplasia, meningoencephalocele, anencephaly, hydrocephaly, holoprosencephaly, Arnold-Chiari malformation, hypoplasia of corpus callosum, aplasia of corpus callosum, defective falx cerebri, frontal lobe defect, migration defect, arachnoid cyst, myelomeningocele, ocular hypertelorism, epicanthal folds, short palpebral fissures, iris coloboma, cataract, corneal clouding, abnormal retinal pigmentation, short nose with upturned nares, choanal atresia, narrow palatal arch, cleft lip, cleft palate, preauricular tags, camptodactyly, limited hip abduction, narrow pelvis, short sternum, short neck with excessive skin folds, dorsiflexed great toes, hypoplastic nails, radial aplasia, radial hypoplasia, thumb aplasia, syndactyly of the second and third digits, arthrogryposis, rocker-bottom feet with prominent calcanei, talipes equinovarus, ventricular septal defects, poly-valvular heart disease, pulmonary valve defects, aortic valve defects, atrial septal defects, patent ductus arteriosus, overriding aorta, coarctation of aorta, hypoplastic left heart syndrome, tetralogy of Fallot, transposition of great arteries, pulmonary hypoplasia, abnormal lobation of lung, omphalocele, malrotation of the intestine, ileal atresia, common mesentery, Meckel diverticulum, esophageal atresia, tracheoesophageal fistula, diaphragmatic eventration, prune belly anomaly, diastasis recti, absent gallbladder, absent appendix, accessory spleens, exstrophy of Cloaca, pyloric stenosis, imperforate anus, malpositioned anus, pilonidal sinus, hernias, micro multicystic kidneys, double ureters, megaloureters, hydroureters, hydronephrosis, horseshoe kidneys, unilateral renal agenesis, cryptorchidism, hypospadias, micropenis, hypoplasia of labia, hypoplasia of ovaries, hypoplastic ovaries, clitoral hypertrophy, bifid uterus, thymic hypoplasia, thyroid hypoplasia, adrenal hypoplasia, clinodactyly of the fifth fingers, single flexion crease, transverse palmar crease, increased atd angle, postzygotic mitotic errors

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Contributor Information and Disclosures

Author

Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, Pathology, Director of Perinatal Genetics and Genetic Laboratory Services, Louisiana State University Medical Center; Laboratory Director, Hema-Con Cancer Cytogenetics Laboratory, Gainesville, Florida
Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, and Teratology Society
Disclosure: Nothing to disclose.

Medical Editor

Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College
Michael Fasullo, PhD is a member of the following medical societies: Radiation Research Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia
David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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