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Trisomy 18: Practice Essentials, Pathophysiology, Epidemiology

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Practice Essentials

Trisomy 18 is characterized by severe psychomotor and growth retardation, microcephaly, microphthalmia, malformed ears, micrognathia or retrognathia, microstomia, distinctively clenched fingers, and other congenital malformations. [1] Among liveborn children, it is the second most common autosomal trisomy after trisomy 21.

Trisomy 18 was independently described by Edwards et al and Smith et al, in 1960. [2, 3]  See the images below.

Note the microphthalmia, micrognathia/retrognathia

Note the microphthalmia, micrognathia/retrognathia, microstomia, low-set/malformed ears, short sternum, and abnormally clenched fingers in an infant with trisomy 18 (Edwards syndrome).

Note the characteristic clenched hand of trisomy 1

Note the characteristic clenched hand of trisomy 18 (Edwards syndrome) with the index finger overriding the middle finger and the fifth finger overriding the fourth finger.

Note the rocker-bottom foot with a prominent calca

Note the rocker-bottom foot with a prominent calcaneus in an infant with trisomy 18 (Edwards syndrome).

This photo shows the hands of a fetus with trisomy

This photo shows the hands of a fetus with trisomy 18 (Edwards syndrome). Note that hands typically present with overlapping digits, in which the second and fifth fingers override the third and fourth fingers, respectively. The overall posturing of the wrists and fingers in this fetus is suggestive of contractures.

Workup in trisomy 18

First-trimester, noninvasive screening based on maternal age, serum markers, and sonographic “soft markers” has demonstrated a high sensitivity for the diagnosis of trisomy 18, [4, 5, 6] and it is now being applied routinely. [1]

Amniocentesis is routinely recommended at 14-16 weeks’ gestation when trisomy 18 is suspected. It remains the criterion standard with which all other invasive diagnostic tests are compared.

Hematologic studies in patients with trisomy 18 during the first week of life include those for thrombocytopenia, neutropenia, and abnormal erythrocyte values.

Fluorescence in situ hybridization (FISH) for rapid diagnosis (most laboratories, ≤24 hours) is more sensitive for mosaicism in the neonatal period (if unknown prenatally), followed by karyotyping, which is necessary even if FISH confirms the diagnosis for the rare translocation; karyotyping is also necessary if the diagnosis is made prenatally to confirm the type of trisomy 18.

Imaging studies include the following:

  • Prenatal ultrasonography - Ultrasonographic abnormalities include microcephaly and Dandy-Walker malformation (posterior fossa enlargement associated with cerebellar hypoplasia)

  • Fetal echocardiography - Abnormal cardiac findings are detectable using echocardiography in most patients with trisomy 18

Management of trisomy 18

Treat infections as appropriate. These are usually secondary to otitis media, upper respiratory tract infections (eg, bronchitis, pneumonia), and urinary tract infection. Sepsis is an ongoing concern.

Provide nasogastric and gastrostomy supplementation for feeding problems.

Orthopedic management of scoliosis may be needed secondary to hemivertebrae. Cardiac management is primarily medical.

Because of the extremely poor prognosis, surgical repair of severe congenital anomalies such as esophageal atresia or congenital heart defects may not be considered and should be discussed with parents.

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Pathophysiology

See the list below:

  • 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.

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Epidemiology

Frequency

United States

Prevalence is approximately 1 in 6000-8000 live births.

At the time of first trimester screening, the incidence of trisomy 18 is 1 in 400, but due to high spontaneous loss, the birth prevalence is 1 in 6500.

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.

For liveborn infants with trisomy 18, the estimated probability of survival to age 1 month was 38.6% and to age 1 year was 8.4%. Median survival time was 14.5 days (population based study). [7]  Nonetheless, in a multistate study of 1113 children with trisomy 18, Meyer et al found a 5-year survival rate of 12.3%. In the study, gestational age had the greatest impact on mortality, while the lowest mortality rates were found among females and the children of non-Hispanic black mothers. [8]  Long-term survival up to age 27 years has been reported. [9, 10, 11]

The high mortality rate in trisomy 18 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.

A retrospective Japanese study by Tamaki et al found that patients with trisomy 18 who were born between 2013 and 2017 (late period [LP] patients) had significantly better 1-year survival rates and survival-to-discharge rates than did those born between 2008 and 2012 (early period [EP] patients). The investigators suggested that these changes may have resulted because surgical intervention rates in trisomy 18 rose significantly, particularly for congenital heart defects. Collecting data from a single pediatric tertiary referral center, the study looked at patients admitted to the center within the first 7 days following birth. The investigators found the 1-year survival rates in the EP and LP groups to be 34.5% and 59.3%, respectively, while the survival-to-discharge rates were 27.6% and 81.5%, respectively. The surgical intervention rates in the EP and LP groups were 59% and 96%, respectively. [12]

Race

Trisomy 18 has no racial predilection.

Sex

Approximately 80% of trisomy 18 cases occur in females. The preponderance of females with trisomy 18 among liveborn infants [7, 13] (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. [14, 15, 16]

Age

Trisomy 18 is detectable during the prenatal and newborn periods.

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Author

Mithilesh Kumar Lal, MD, MBBS, MRCP, FRCPCH, MRCPCH(UK) Consultant Neonatologist, Clinical Director for Neonatal Services, Associate Medical Director (Revalidation), The James Cook University Hospital, South Tees Foundation NHS Trust; UK Chair, Theory MRCPCH Exams, Senior Clinical MRCPCH Examiner, Royal College of Pediatrics and Child Health (UK)

Mithilesh Kumar Lal, MD, MBBS, MRCP, FRCPCH, MRCPCH(UK) is a member of the following medical societies: American Pediatric Society, Society for Pediatric Research, British Association of Perinatal Medicine, British Medical Association, Neonatal Society, Nepal Medical Association, Royal College of Paediatrics and Child Health, Royal College of Physicians

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD, PhD, FAAP, FACMG Deputy Chief, Department of Pediatrics, Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD, PhD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Harold Chen, MD, MS, FAAP, FACMG Professor, Department of Pediatrics, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics

Disclosure: Nothing to disclose.