Review

Trisomy 18: review of the clinical, etiologic, prognostic, and ethical aspects
Trissomia 18: revisão dos aspectos clínicos, etiológicos, prognósticos e éticos
Trisomía 18 (síndrome de Edwards): revisión de los aspectos clínicos, etiológicos, pronósticos y éticos

Rafael Fabiano M. Rosa1, Rosana Cardoso M. Rosa2, Paulo Ricardo G. Zen3, Carla Graziadio4, Giorgio Adriano Paskulin5

ABSTRACT Often, interventions are performed under emergency condi-

tions, without many opportunities for discussion, and they
Objective: To review the clinical, etiological, diagnos- involve difficult medical and ethical issues.
tic, and prognostic characteristics of trisomy 18 (Edwards
syndrome). Key-words: chromosomes, human, pair 18; trisomy;
Data sources: Scientific articles in the MedLine, Lilacs, chromosome aberrations; survival analysis; prognosis.
and SciELO databases were searched using the descriptors
‘trisomy 18’ and ‘Edwards syndrome’. The research was not RESUMO
limited to a specific time period and included all articles
in such databases. Objetivo: Revisar as características clínicas, etiológicas,
Data synthesis: Edwards syndrome is a disease character- diagnósticas e prognósticas da trissomia do cromossomo 18
ized by a broad clinical picture and a very reserved prognosis. (síndrome de Edwards).
There are descriptions of more than 130 different anomalies, Fontes de dados: Foram pesquisados artigos científicos
which can involve virtually all organs and systems. Its find- presentes nos portais MedLine, Lilacs e SciELO, utilizando-se
ings are the result of the presence of three copies of chro- os descritores ‘trisomy 18’ e ‘Edwards syndrome’. A pesquisa
mosome 18. The main chromosomal constitution observed não se limitou a um período determinado e englobou artigos
among these patients is a free trisomy of chromosome 18, presentes nestes bancos de dados.
which is associated with the phenomenon of nondisjunction, Síntese dos dados: A síndrome de Edwards é uma doença
especially in maternal gametogenesis. Most fetuses with caracterizada por um quadro clínico amplo e prognóstico
Edwards syndrome die during the embryonic and fetal life. bastante reservado. Há descrição na literatura de mais
The median of survival among live births has usually varied de 130 anomalias diferentes, as quais podem envolver
between 2.5 and 14.5 days. praticamente todos os órgãos e sistemas. Seus achados são
Conclusions: Knowledge on the clinical picture and on resultantes da presença de três cópias do cromossomo 18.
the prognosis of Edwards syndrome patients is of great im- A principal constituição cromossômica observada entre
portance regarding the neonatal care and the decisions about estes pacientes é a trissomia livre do cromossomo 18, que
invasive treatments. The speed to have a confirmed diagnosis se associa ao fenômeno de não disjunção, especialmente na
is important for making decisions about medical procedures. gametogênese materna. A maioria dos fetos com síndrome

Instituições: Universidade Federal de Ciências da Saúde de Porto Alegre Endereço para correspondência:
(UFCSPA); Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Giorgio Adriano Paskulin
Porto Alegre, RS, Brasil Rua Sarmento Leite, 245, sala 403 – Centro
1
Doutor pelo Programa de Pós-Graduação em Patologia da UFCSPA; CEP 90050-170 – Porto Alegre/RS
Geneticista Clínico do Hospital Materno Infantil Presidente Vargas (HMIPV), E-mail: [email protected]
Porto Alegre, RS, Brasil
2
Doutoranda pelo Programa de Pós-Graduação em Patologia da UFCSPA, Fonte financiadora: Coordenação de Aperfeiçoamento de Pessoal de Nível
Porto Alegre, RS, Brasil Superior (Capes)
3
Doutor pelo Programa de Pós-Graduação em Patologia da UFCSPA; Conflito de interesse: nada a declarar
Professor-Adjunto da Disciplina de Genética Clínica da UFCSPA, Porto
Alegre, RS, Brasil Recebido em: 22/2/2012
4
Doutoranda pelo Programa de Pós-Graduação em Patologia da UFCSPA; Aprovado em: 21/5/2012
Professora-Assistente da Disciplina de Genética Clínica da UFCSPA, Porto
Alegre, RS, Brasil
5
Doutor pelo Programa de Pós-Graduação em Genética e Biologia Molecular
da Universidade Federal do Rio Grande do Sul (UFRGS); Professor-Associado
da Disciplina de Genética Clínica da UFCSPA, Porto Alegre, RS, Brasil

Rev Paul Pediatr 2013;31(1):111-20.

 Trisomy 18: review of the clinical, etiologic, prognostic, and ethical aspects

de Edwards acaba indo a óbito durante a vida embrionária sin muchas oportunidades de reflexión o discusión, e implican
e fetal. A mediana de sobrevida entre nascidos vivos tem cuestiones médicas y éticas difíciles.
usualmente variado entre 2,5 e 14,5 dias.
Conclusões: O conhecimento do quadro clínico e do Palabras clave: cromosomas humanos par 18; trisomía;
prognóstico dos pacientes com a síndrome de Edwards aberraciones cromosómicas; análisis de sobrevida; pronóstico.
tem grande importância no que diz respeito aos cuidados
neonatais e à decisão de instituir ou não tratamentos invasi- Introduction
vos. A rapidez na confirmação do diagnóstico é importante
para a tomada de decisões referentes às condutas médicas. Trisomy 18 was first described in 1960 by Edwards et al, who
Muitas vezes, as intervenções são realizadas em condições reported a newborn with multiple malformations and cogni-
de emergência, sem muita oportunidade de reflexão ou tive impairment(1). Interestingly, unlike Down syndrome, the
discussão, e envolvem questões médicas e éticas difíceis. syndrome had never been recognized as a distinct clinical entity
until then(2). Edwards et al reported a “new trisomy syndrome”,
Palavras-chave: cromossomos humanos par 18; tris- which was first named as “17-18 trisomy”. That occurred
somia; aberrações cromossômicas; análise de sobrevida; due to the difficulties in differentiating the pair of autosomal
prognóstico. chromosomes(1). By that time, autosomal chromosomes were
classified based on the length and the position of the centro-
RESUMEN mere, and were subdivided into categories assigned by letters
from A to G(3). Shortly after the description of the syndrome,
Objetivo: Revisar las características clínicas, etiológicas, in 1960, Smith et al(4) showed that the additional chromosome
diagnósticas y pronósticas de la trisomía del cromosoma 18 was the chromosome 18. In the following years, several other
(síndrome de Edwards). different chromosomal constitutions associated with Edwards
Fuentes de datos: Fueron investigados artículos científi- syndrome (ES) were reported, such as trisomy 18 mosaicism,
cos presentes en los portales MedLine, Lilacs y SciELO, utili- double aneuploidy (i.e., trisomy 18 associated with other nu-
zando los descriptores “trisomy 18” y “Edwards syndrome”. merical changes of autosomal and sexual chromosomes) as well
La investigación no se limitó a un periodo determinado y as structural anomalies, such as translocations.
abarcó artículos presentes en estas bases de datos. ES is one of the most frequent autosomal trisomies observed
Síntesis de los datos: La síndrome de Edwards es una at birth, second only to Down syndrome (trisomy of the
enfermedad caracterizada por un cuadro clínico amplio y chromosome 21). Its importance lies on its high prevalence,
pronóstico bastante reservado. Hay descripción en la litera- estimated from 1: 3600–1:8500 live births in different areas of
tura de más de 130 anomalías distintas, que pueden implicar the world, such as North America, Europe and Australia(5-10).
a prácticamente todos los órganos y sistemas. Sus hallazgos In trisomy 18, a predominance of affected females is observed,
son resultantes de la presencia de tres copias del cromosoma in the ratio of almost 1 male to 2 females(7,11-13). Some authors,
18. La principal constitución cromosómica observada entre however, have reported an equal frequency of genders in fetal
estos pacientes es la trisomía libre del cromosoma 18, que evaluations(9), mainly before the 18th gestational week(14).
se asocia al fenómeno de no disyunción, especialmente en la
gametogénesis materna. La mayoría de los fetos con síndrome Clinical Manifestations
de Edwards evoluciona a óbito durante la vida embrionaria y
fetal. La mediana de sobrevida entre los nacidos vivos tiene ES is characterized by variable clinical manifestations,
usualmente variado entre 2,5 y 14,5 días. with involvement of multiple organs and systems. More than
Conclusiones: El conocimiento del cuadro clínico y del 130 different anomalies have been reported in the literature,
pronóstico de los pacientes con el síndrome de Edwards tiene which may affect virtually all organs and systems, none of which
gran importancia en lo que se refiere a los cuidados neonatales y is pathognomonic of trisomy 18(2,15-18). The most frequent
a la decisión de instituir o no tratamientos invasivos. La rapidez phenotypic characteristics of the syndrome, according to the
en la confirmación del diagnóstico es importante para la toma topography, consist of: neurological findings, growth distur-
de decisiones referentes a las conductas médicas. Muchas veces, bances, malformations of the skull, face, thorax, abdomen,
las intervenciones son realizadas en condiciones de emergencia, limbs, genitals, skin, skin annexes, and internal organs.

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 Rafael Fabiano M. Rosa et al

Neurological findings associated with preauricular tags. Cleft lip is reported in 5%

Mental retardation is frequent and usually severe in this of cases, and cleft palate in other 5%. Choanal atresia may
syndrome. The hypotonia, observed in the neonatal period, also be present(2,13,16,17).
is followed by hypertonia. The cry is weak and the response Less frequent anomalies include wide fontanels, hypopla-
to sounds is reduced. Suction difficulties are common. sia of the supracilliary ridges, Wormian bones, eye abnor-
Severe cognitive and motor development dysfunction is the malities such as corneal opacities, microphtalmia, coloboma,
rule(16,17,19). Nevertheless, individuals with ES usually reach cataract, glaucoma, blue sclera, oblique or narrow palpebral
some degree of psychomotor maturity and keep learning fissures, epicanthic folds, ptosis, abnormally thickened eye-
continuously(19). Interestingly, cases of trisomy 18 mosaicism lids, abnormally long or sparse eyelashes, blepharophimosis,
with normal intelligence have been reported(20). hypertelorism, strabismus and nystagmus(2,16,17).

Growth Thorax and abdomen

Low birth weight is common, and followed by failure to Short neck with excess hair, short sternum, small nipples,
thrive. The hypoplasia of the subcutaneous, fat, and skeletal umbilical or inguinal hernia and/or diastasis of the rectus
muscles is characteristic(2,16,17). Growth curves specific for muscles, narrow pelvis and limitation of the hip abduction
trisomy 18 patients can be found in the literature(21). may be noticed. The chest may be relatively wide, with
or without widely spaced nipples. Other findings include
Skull and face incomplete ossification of the clavicle, hemivertebrae, fused
The skull of patients with ES is dysmorphic, with narrow vertebrae, scoliosis, rib anomalies, pectus excavatum and
bifrontal diameter and prominent occipitus; enlarged fonta- hip dislocation(2,16).
nels and microcephaly may be present. The face shows a tri-
angular shape, and the forehead is high and wide. Palpebral Extremities
fissures are narrow, the nose and mouth are small, the palate Typically, the fists are clenched, with overlapping of
is narrow and high, and there is micrognathia. The ears are the second over the third and of the fifth over the fourth
dysplastic and low-set, resembling faun ears, and may be fingers(2,16,17) (Figure 1). The distal crease of the fifth finger

Figure 1 - Hands of a patient with Edwards syndrome. Note the clenched fists with overlapping fingers and the hypoplasia of the nails

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 Trisomy 18: review of the clinical, etiologic, prognostic, and ethical aspects

and, less frequently, of the third and fourth fingers may be Regarding the intra-abdominal organs, several types of re-
lacking. Analysis of the dermatoglyphics usually shows a nal abnormalities have been observed, the most frequent be-
pattern of increased arches at the digital pulps of six or more ing the horseshoe, polycystic, ectopic or hypoplastic kidneys,
fingers. Single palmar crease and clinodactyly of the fifth renal agenesis, hydronephrosis, hydroureter and ureteral
fingers may also be present(2,16). The nails are hypoplastic. duplication(16,17,22). Malformations of the digestive system
Clubfoot and prominent calcaneus are common, and there include esophageal atresia with or without tracheoesophageal
may be rocker-bottom (or rocking chair) foot. The hallux
is shortened and dorsiflexed. Syndactyly of the second and Table 1 - Frequently observed anomalies in patients with trisomy
18, based on Marion et al(15); Hodes et al(16) and Kinoshita et al(17)
third toes is also a common finding(2,16,17). Less frequent
anomalies include syndactyly of the third and fourth fingers, Alterations
polydactyly, ectrodactyly, thumb aplasia and hypoplasia/
Growth
aplasia of the radius(16,17).
Failure to thrive
Central nervous system
Genitals
Neurodevelopmental delay
Cryptorchidism, clitoral hypertrophy with hypoplasia
Hypertonia
of the labia majora and ovaries are common. Hypospadia,
Skul and face
micropenis, ovarian or gonadal dysgenesis, and bifid uterus
Prominent occipitus
may also be observed(2,16,17).
Micrognathia
Dysplasic, low-set ears
Skin and cutaneous annexes
Redundancy of the skin, hirsutism of the forehead and Microcephaly
the back, prominent cutis marmorata and hemangiomas can Thorax
be observed. Hypomelanosis of Ito and skin abnormalities Widened spaced nipples
along the Blaschko´s lines have also been described(2,16,17). Heart deffects
Ventricular sept defects
Internal organs malformations Patent ductus arteriosus
Central nervous system malformations occur in nearly Patente foramen ovale
30% of cases, with frequent cerebellar hypoplasia, heterotopy Polivalvular heart disease
of the granule cells in the white matter, and anomalies of the Abdomen
corpus callosum. Other abnormalities include hydrocepha- Umbilical/inguinal hernia
lus, anencephaly, myelomeningocele, facial palsy, Arnold- Ectopic pancreas
Chiari malformation, arachnoid cysts and periventricular Meckel´s diverticulum
heterotopia of the brain(16,17). Urogenital
Congenital heart defects are often described and are Cryptorchidism
considered almost a rule. The frequency of heart defects Prominent clitoris
reported in autopsies and echocardiography studies is simi- Renal deffects
lar (usually greater than 90%)(9,10,17,21-23). A wide spectrum
Horseshoe kidney
of heart defects is reported in patients with ES, with most
Cystic kidneys
individuals presenting with multiple defects. Ventricular
Limbs
septal defects and patent ductus arteriosus were described
Hypoplastic nails
in the original report of Edwards et al(1), and are considered
Camptodactyly of the fingers
as major anomalies, frequently described in the literature.
Clubfoot
Polivalvular heart disease (characterized by the involvement
of two or more atrioventricular and/or semilunar valves) is Prominent calcaneous
considered by some authors as a characteristic finding, which Dorsiflexed halux
has been described in some case series of patients with ES in Rocker-bottom foot
100% of cases(13,17,22,24). Syndactyly of the second and third toes

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 Rafael Fabiano M. Rosa et al

fistula, omphalocele, pyloric stenosis, extra-hepatic biliary meiotic non-disjunction of the maternal meiosis phase II.
atresia, ileal atresia, Meckel´s diverticulum and intestinal Interestingly, in other trisomies the defects commonly occur
malrotation. Thyroglossal duct cyst, hypoplastic gallbladder, during the meiosis phase I(31).
gallstones, abnormal liver lobulation, heterotopic pancreas, Chromosomal translocations can happen as new anomalies
incomplete fixation of the colon, agenesis of the appendix, (de novo) or can be transmitted within a family. The chromo-
accessory spleen, cloacal exstrophy, diaphragmatic eventra- somal mosaicism, in the other hand, is always a post-zygotic
tion, diaphragmatic hernia, imperforate or misplaced anus event. The main cause is the mitotic non-disjunction that can
can also be observed. occur in any phase of the embryogenesis or development(32).
The most frequent anomaly in the organs of the immune
system is the atrophy or hypoplasia of the thymus. The Diagnosis
decreased lymphocyte count in the spleen, lymph nodes
and intestinal tract has also been described. Agenesis or The clinical features of ES are very singular, and it
segmentation defects of the right lung, thyroid or adrenal is rarely confused with other conditions. Marion et al(15)
hypoplasia may be present(2,16,17), as noted in Table 1. developed a scoring system aiming to optimize its identi-
Several neoplastic diseases have been occasionally reported fication in the neonatal period. Their goal was to create a
in individuals with ES and include Wilms´ tumor(25) and method to help the physician with no specific training in
hepatoblastoma(26). clinical genetics and dysmorphology to differentiate the
newborns with the syndrome from other children with
Pathophisiology multiple congenital defects(15).
The diagnosis of ES is usually confirmed by the karyo-
It is important to note that the abnormalities presented type test showing either partial or complete trisomy of the
by the patients result from the additional genetic mate- chromosome 18. More recently, other techniques such as the
rial of the chromosome 18, and there is controversy in the fluorescent in situ hybridization (FISH) and the comparative
literature regarding the critical region for the syndrome(27). genomic hybridization (CGH) have been used to detect
For instance, the region 18q21.1→qter is considered critical patients with trisomy 18, especially in specific situations
by some authors, as its duplication is enough to result in such as the rapid diagnosis of newborn babies or prenatal
the ES phenotype(28). Other authors consider the 18q12 as diagnosis. The first descriptions on the use of these tech-
the critical region. According to Boghosian-Sell et al, there niques date back to the mid-eighties. The FISH test can also
are two critical regions, a proximal (18q12→q21.2) and a be performed in tissues fixed in formalin and embedded in
distal one (18q22.3→qter), which act together to produce paraffin(33). The sequencing of fetal DNA molecules in the
the typical phenotype of the trisomy 18(27). maternal blood has also emerged as an accurate and non-
The less severe, nonspecific phenotype of patients with invasive form of prenatal diagnosis(34).
mosaicism seems to be related to the proportion of normal About 90 to 95% of patients with ES have the chromo-
cells in the organism of the affected individual. However, somal constitution of free trisomy of the chromosome 18; less
some authors have not observed this association. In some than 10% present a translocation that involves the chromo-
instances, patients with trisomy 18 may present unusual some 18 which results in the trisomy, or mosaicism, which
clinical manifestations, making the diagnosis a challenge(18). shows the chromosomal constitution of a lineage of trisomy
The discrepancies in the phenotype can even be observed 18, usually associated with a normal lineage. Double aneu-
between monozygotic twins(29). ploidy, i.e., the presence of a chromosomal constitution of
trisomy 18 associated with another aneuploidy (for instance,
Etiology of the chromosome X) is considered rare.
The first reports of prenatal diagnosis of trisomy 18 date to
In ES, as well as in other trisomies, maternal age is the early 70´s. Currently, the suspicion of ES in the neonatal
usually older(6,9,13,17,30). There is no doubt in the literature period can be done by fetal ultrasound (including the nuchal
that this is the most important predisposing factor for the translucence), biochemical analysis (showing reduced levels
non-disjunction of the chromosomes in the process of cell of human chorionic gonadotropin, alpha-fetoprotein and
division. Most cases of trisomy 18 occur due to the de novo unconjugated estriol in the maternal serum during the first

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 Trisomy 18: review of the clinical, etiologic, prognostic, and ethical aspects

and second gestational trimesters), and confirmed by fetal The frequency of cesarean deliveries is quite high
chromosomal analysis obtained by chorionic villus puncture in pregnancies of fetuses with ES, ranging from 48 to
and amniocentesis(35). 90%(6,9,12,13,23,30) and some studies particularly highlight this
Fetal echocardiography, especially when performed by aspect(12). Interestingly, few maternal complications during
the 20th gestational week, can detect heart defects sugges- pregnancy have been reported. Preeclampsia has been de-
tive of trisomy 18. It is considered an essential method for scribed in 12.5 to 17% of mothers of fetuses with ES(17,22,30).
the diagnosis of the syndrome, once the echocardiographic Preterm birth, with low birth weight and low first and fifth
finding of heart defects is considered the most sensitive minutes Apgar scores are also frequent among children with
for the diagnosis of the syndrome after the 16th gestational ES(6,9,13,17,21,30).
week. Other common manifestations reported during preg-
nancy can be observed in Table 2. Szigeti et al report that Differential diagnosis
perinatal autopsy can provide additional information in The differential diagnosis of ES is relatively wide, and
fetuses with ES and may help the diagnosis(37). According includes conditions such as the fetal akinesia sequence (also
to Viora et al, the modern ultrasound examination is clearly called Pena-Shokeir syndrome type I), and Patau´s syn-
highly sensitive (sensitivity > 90%) to detect fetuses with drome. Due to the defects of the hands, some cases may be
this syndrome(36). misinterpreted as the so-called distal arthrogryposis type I.
In Brazil, the identification of patients with trisomy 18 Other conditions to be considered in the differential diag-
during prenatal care is especially important for planning the nosis, due to the overlapping of some malformations, are
birth, since termination of pregnancy is not legally allowed the CHARGE syndrome, previously named as CHARGE
(it may only be permitted in cases of risk to the mother´s association (Coloboma, congenital Heart defects, choanal Atresia,
life or when there is a history of sexual violence)(38). Retardation of growth, Genital and Ear abnormalities) and the
VACTERL association (Vertebral defects, Anal atresia, Cardiac
Table 2 - Abnormalities that can be observed at ultrasound in malformations, Tracheoesophageal fistula with Esophageal atresia,
fetuses with trisomy 18, based on Viora et al(36)
Renal dysplasia, and Limb anomalies).
Abnormalities detected on ultrasound
Polydramnius/oligohydramnius Prognosis
Intrauterine growth restriction
Single umbilical artery Most of the fetuses with ES do not survive to the end of
the gestational period. Those who are born alive have a poor
Central nervous system
prognosis. The median survival reported in the literature
Abnormally shaped head (strawberry or lemon shape)
ranges from 2.5 to 14.5 days. In general, 55–65% of the
Dandy-Walker malformation affected newborns die during the first week, 90% in six
Choroid plexus cysts months, and only 5–10% reach the end of the first year of
Neural tube deffects life(5-11,13,24,30,39-41), as shown in Table 3.
Micrognathia The findings of Lin et al(13), in agreement with Weber(11),
Cystic hygroma or lymphangiectasy Carter et al(5), Baty et al(21), Root and Carey(8), Embleton et al(9),
Rasmussen et al(10) and Niedrist et al(24) suggest that the girls
Omphalocele
with ES have greater chances of being born alive and survive
Esophageal atresia
for longer periods than the boys. Moreover, some cases of
Heart defects ES seem to have a longer survival due to a chromosomal
Renal anomalies constitution of mosaicism(10).
Limbs anomalies In the other hand, long term survival (in a few cases,
Clenched fists with overlapping fingers longer than two decades) is well documented, even in the
Radius abnormalities absence of mosaicism, mostly in non populational studies
(most of them, case reports). However, it is important to
Rocker-bottom foot
note that these patients usually present with severe neuro-
Clubfoot
developmental delay and high dependency(42).

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 Table 3 - Data on survival of patients with trisomy 18 born alive according to studies from different countries

Carter Young Goldstein e Root e Embleton Brewer Rasmussen Niedrist Lin Imataka Hsiao Rosa
Author Weber (11)
et al(5) et al (6) Nielson (7) Carey (8) et al(9) et al(39) et al(10) et al(24) et al(13) et al(40) et al(41) et al(30)

n 192 43 21 76 64 34 84 114 161 39 179 31 31

United
USA Australia Denmark USA England Scotland USA Switzerland Taiwan Japan Taiwan Brazil

Rev Paul Pediatr 2013;31(1):111-20.

Country Kingdom

% % % % % % % % % % % % %

Birth 100 100 100 100 100 100 100 100 100 100 100 100 100

1 day 98 60 67 60 86 70 88 86 68 95 85 90

1 week 89 35 32 44 45 43 63 40 46 69 58

2 weeks 81 15 32 41 50 31 27 45

1 month 72 11 18 21 34 15 25 39 22 16 32 52

2 months 53 8 22 30 17 11 36 14 32

3 months 38 5 20 6 21 14 5 23

4 months 30 14 19 12 5 19

5 months 23 0 9 12 9 3
Rafael Fabiano M. Rosa et al

6 months 13 5 3 9 11 9 3 18 10 13

1 year 8 4 5 0 2 8 6 3 9 6 6

2 years 5 0 5 4 3 6 3

3 years 3 5 3 3 3

4 years 2 5 2 3

5 years 1 3 2 3

6 years 0.3 3 1 3

Median of 70 5 2.5 6 4 3 6 14.5 4 6 UD 12 31

SV (days)

n: sample size; USA: United States of America; SV: survival; UD: undetermined

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 Trisomy 18: review of the clinical, etiologic, prognostic, and ethical aspects

Tanigawa et al found that some ultrasound findings are in the long term follow up of patients with ES(47). Thus, it
associated to less than one month survival(43). Such findings is unclear whether heart surgery improves the prognosis of
consist of severe polyhydramnios, lack of fluids in the stom- these individuals(46). Patients with ES present several risk
ach, major heart defects, and male gender. Gestational age on factors for developing sepsis, an important cause of death,
birth also seems to affect survival(8,10,24). Some recent studies which include low birth weight, prematurity, multiple
have shown survival rates lower than previously reported, malformations, associated with long intensive care stay and
possibly due to the less aggressive care of children with ES, the consequent invasive procedures, which favor the devel-
related to the short survival expectancy(10). opment of infections.
In addition, previous studies have shown that the pres- In Brazil there are no specific guidelines on cardio-
ence of congenital heart defects do not influence the survival vascular resuscitation of newborns with ES, neither in
of patients with ES(9,10). More recently, Niedrist et al also the delivery room nor later. However, according to the
found, in a Swiss cohort study, that heart defects have little Neonatal Resuscitation Program of Sociedade Brasileira de
or no influence on survival(24). In the past, apnea and no Pediatria(48), medical decisions in the delivery room need
therapeutical investment were considered the major causes to be supported by the prenatal diagnosis, and take into
of death(9). According to Kaneko et al, patients older than consideration the parents’ wishes and the recent thera-
one month usually die due to complications of the congenital peutic advances. The ‘wait to see’ strategy before starting
heart defect (apnea is a common cause among neonates in the resuscitation should be abandoned, as it may lead to
the first week of life)(44). However, recent studies indicate deleterious consequences such as hypoxemia and hypoten-
that congenital heart defects are the leading cause of death sion, which further increase morbidity and mortality. As
in intensive care patients(23,45). Thus, intensive management, reported by Rosa et al(30), the prenatal diagnosis of ES in
including heart surgery, can improve the survival of patients Brazil is still poor, which has important implications on
with the syndrome(45). Indeed, studies that evaluated patients the management of these patients. In their series of 31
receiving neonatal intensive care have shown median survival consecutive patients evaluated in a referral hospital in
longer than usual, ranging from 152.5 to 238 days(23,45). southern Brazil, Rosa et al found that none of them had
Heart surgery is rarely performed in patients with ES. been diagnosed prenatally(30).
However, indications of heart surgery have been growing in Interestingly, the choice for performing cardiopulmonary
the recent years. This seems to be related to a change in the resuscitation can be influenced, for instance, by cultural
behavior of healthcare providers towards greater acceptance factors. In the evaluation of patients born in Taiwan from
on the autonomy of the parents regarding treatment deci- 1991 to 2003, Hsiao et al(41) did not find any differences on
sions(44). To date, there are no well-defined criteria of heart survival between the genders in individuals with ES, and
surgery indications in this group of patients. Most individu- attributed this observation to the more frequent no consent
als survive to palliative and corrective surgeries. However, for resuscitation for female newborns (bearing in mind that
the risk of complications consequent to surgical corrections the male sex is favored in relation to the female sex among
of the heart defects, as well as the risk of death from other traditional Chinese families).
causes, is high(46). Therefore, as stated by Yamagishi, guide-
lines for the treatment of such patients are needed(46). Genetic Couseling
Heart surgery can improve life expectancy, allow the
hospital discharge and improve the quality of life of patients The diagnostic and etiological evaluation of the syndrome
and their families(46). Some limitations, however, can be ob- are important not only for the adequate management of these
served among the studies that support these results, such as individuals, but also for the proper genetic counseling of the
the small sample sizes and the selection of patients with less families. In cases of free trisomy 18 there is no indication
severe cardiac and extracardiac defects(44,46,47). Yamagishi(46) for the cytogenetic evaluation of the parents because, as
and Muneuchi(47) have reported that selected individuals previously stated, this anomaly results from the phenom-
can benefit from the surgical correction of heart defects, enon of non-disjunction during the gametogenesis. Some
and the indication of such procedure should be carefully authors suggest that there is a slight increased risk in further
individualized. Nevertheless, few studies have evaluated the pregnancies, even for potentially viable trisomies, and that
effectiveness of heart surgery and the further quality of life certain women present a predisposition for meiotic errors

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 Rafael Fabiano M. Rosa et al

in general. However, the recurrence of the same trisomy in to a new (de novo) mutation, although the possibility of
another child has only rarely been reported, and the risk is germinative mosaicism cannot be ruled out.
considered virtually unknown. Some studies point a risk
from 0.5% to less than 1%(21). Those estimates were based Conclusions
mainly on the risk for nondisjunction, which was empirically
calculated for trisomy 21. The knowledge of the clinical features and prognosis of
Uehara et al found that none of the 170 women who had patients with ES is of great importance regarding the neona-
a child with trisomy 18 had the same anomaly repeated in a tal care and the decision of performing invasive procedures,
further pregnancy(49). However, it is important to take into such as heart surgery or cardiopulmonary resuscitation.
consideration the increased risk of trisomies with advancing The early diagnostic confirmation is important for mak-
maternal age. Moreover, one cannot rule out the possibility ing medical decisions. Often, interventions are performed
of gonadal mosaicism, especially in recurrent cases. under emergency conditions, leaving little opportunity for
In the other hand, in cases of trisomy 18 due to transloca- reflections or discussion, and involve difficult medical and
tion, the chromosomal analysis of the parents is indicated, ethical issues.
in order to rule out the presence of a balanced chromosomal
rearrangement in one of them. In that case, the risk of recur- Acknowledgements
rence for the couple is increased, depending on the type of
chromosomal anomaly. However, if the parental karyotypes To the Coordenação de Aperfeiçoamento de Pessoal de
are normal, it is assumed that the syndrome occurred due Nível Superior (Capes), for the scholarship given.

References
1. Edwards JH, Harnden DG, Cameron AH, Crosse VM, Wolff OH. A new trisomic 17. Kinoshita M, Nakamura Y, Nakano R, Morimatsu M, Fukuda S, Nishimi Y et  al.
syndrome. Lancet 1960;1:787-90. Thirty-one autopsy cases of trisomy 18: clinical features and pathological
2. Smith DW. Autosomal abnormalities. Am J Obstet Gynecol 1964;90:1055-77. findings. Pediatr Pathol 1989;9:445-57.
3. Patau K. The identification of individual chromosomes, especially in man. Am 18. Zen PR, Rosa RF, Rosa RC, Dale Mulle L, Graziadio C, Paskulin GA. Unusual
J Hum Genet 1960;12:250-76. clinical presentations of patients with Patau and Edwards syndromes: a
4. Smith DW, Patau K, Therman E, Inhorn SL. A new autosomal trisomy syndrome: diagnostic challenge? Rev Paul Pediatr 2008;26:295-9.
multiple congenital anomalies caused by an extra chromosome. J Pediatr 19. Baty BJ, Jorde LB, Blackburn BL, Carey JC. Natural history of trisomy 18 and
1960;57:338-45. trisomy 13: II. Psychomotor development. Am J Med Genet 1994;49:189-94.
5. Carter PE, Pearn JH, Bell J, Martin N, Anderson NG. Survival in trisomy 18. 20. Bettio D, Levi Setti P, Bianchi P, Grazioli V. Trisomy 18 mosaicism in a woman
Life tables for use in genetic counseling and clinical paediatrics. Clin Genet with normal intelligence. Am J Med Genet A 2003;120A:303-4.
1985;27:59-61. 21. Baty BJ, Blackburn BL, Carey JC. Natural history of trisomy 18 and trisomy
6. Young ID, Cook JP, Mehta L. Changing demography of trisomy 18. Arch Dis 13: I. Growth, physical assessment, medical histories, survival, and recurrence
Child 1986;61:1035-6. risk. Am J Med Genet 1994;49:175-88.
7. Goldstein H, Nielsen KG. Rates and survival of individuals with trisomy 13 and 22. Moerman P, Fryns JP, Goddeeris P, Lauweryns JM. Spectrum of clinical and
18. Data from a 10-year period in Denmark. Clin Genet 1988;34:366-72. autopsy findings in trisomy 18 syndrome. J Genet Hum 1982;30:17-38.
8. Root S, Carey JC. Survival in trisomy 18. Am J Med Genet 1994;49:170-4. 23. Kosho T, Nakamura T, Kawame H, Baba A, Tamura M, Fukushima Y. Neonatal
9. Embleton ND, Wyllie JP, Wright MJ, Burn J, Hunter S. Natural history of trisomy management of trisomy 18: clinical details of 24 patients receiving intensive
18. Arch Dis Child Fetal Neonatal Ed 1996;75:F38-41. treatment. Am J Med Genet A 2006;140:937-44.
10. Rasmussen SA, Wong LY, Yang Q, May KM, Friedman JM. Population-based 24. Niedrist D, Riegel M, Achermann J, Schinzel A. Survival with trisomy 18 – data
analyses of mortality in trisomy 13 and trisomy 18. Pediatrics 2003;111:777-84. from Switzerland. Am J Med Genet A 2006;140:952-9.
11. Weber WW. Survival and the sex ratio in trisomy 17-18. Am J Hum Genet 25. Anderson CE, Punnett HH, Huff V, de Chadarévian JP. Characterization
1967;19:369-77. of a Wilms tumor in a 9-year-old girl with trisomy 18. Am J Med Genet A
12. David TJ, Glew S. Morbidity of trisomy 18 includes delivery by caesarean 2003;121:52-5.
section. Lancet 1980;2:1295. 26. Maruyama K, Ikeda H, Koizumi T. Hepatoblastoma associated with trisomy
13. Lin HY, Lin SP, Chen YJ, Hung HY, Kao HA, Hsu CH et al. Clinical characteristics 18 syndrome: a case report and a review of the literature. Pediatr Int 2001;
and survival of trisomy 18 in a medical center in Taipei, 1988-2004. Am J Med 43:302-5.
Genet A 2006;140:945-51. 27. Boghosian-Sell L, Mewar R, Harrison W, Shapiro RM, Zackai EH, Carey J et al.
14. Niedrist D, Riegel M, Achermann J, Rousson V, Schinzel A. Trisomy 18: changes Molecular mapping of the Edwards syndrome phenotype to two noncontiguous
in sex ratio during intrauterine life. Am J Med Genet A 2006;140:2365-7. regions on chromosome 18. Am J Hum Genet 1994;55:476-83.
15. Marion RW, Chitayat D, Hutcheon RG, Neidich JA, Zackai EH, Singer LP et al. 28. Mewar R, Kline AD, Harrison W, Rojas K, Greenberg F, Overhauser J. Clinical
Trisomy 18 score: a rapid, reliable diagnostic test for trisomy 18. J Pediatr and molecular evaluation of four patients with partial duplications of the long
1988;113:45-8. arm of chromosome 18. Am J Hum Genet 1993;53:1269-78.
16. Hodes ME, Cole J, Palmer CG, Reed T. Clinical experience with trisomies 18 29. Schlessel JS, Brown WT, Lysikiewicz A, Schiff R, Zaslav AL. Monozygotic twins
and 13. J Med Genet 1978;15:48-60. with trisomy 18: a report of discordant phenotype. J Med Genet 1990;27:640-2.

119
Rev Paul Pediatr 2013;31(1):111-20.
 Trisomy 18: review of the clinical, etiologic, prognostic, and ethical aspects

30. Rosa RF, Rosa RC, Lorenzen MB, de Moraes FN, Graziadio C, Zen PR et al. 40. Imataka G, Nitta A, Suzumura H, Watanabe H, Yamanouchi H, Arisaka O.
Trisomy 18: experience of a reference hospital from the south of Brazil. Am J Survival of trisomy 18 cases in Japan. Genet Couns 2007;18:303-8.
Med Genet A 2011;155A:1529-35. 41. Hsiao CC, Tsao LY, Chen HN, Chiu HY, Chang WC. Changing clinical
31. Bugge M, Collins A, Petersen MB, Fisher J, Brandt C, Hertz JM et al. Non- presentations and survival pattern in trisomy 18. Pediatr Neonatol 2009;
disjunction of chromosome 18. Hum Mol Genet 1998;7:661-9. 50:147-51.
32. Paskulin GA, Lorenzen MB, Rosa RF, Graziadio C, Zen PR. Importance of the 42. Shanske AL. Trisomy 18 in a second 20-year-old woman. Am J Med Genet A
fibroblast chromosomal analysis in suspected cases of mosaicism: experience 2006;140:966-7.
of a clinical genetics service. Rev Paul Pediatr 2011;29:73-9 43. Tanigawa T, Nakayama D, Miura K, Miura S, Shimada T, Masuzaki H. Prenatal
33. Isaksen CV, Ytterhus B, Skarsvåg S. Detection of trisomy 18 on formalin-fixed ultrasonographic findings may be useful in predicting the prognosis of trisomy
and paraffin-embedded material by fluorescence in situ hybridization. Pediatr 18. Prenat Diagn 2007;27:1039-44.
Dev Pathol 2000;3:249-55. 44. Kaneko Y, Kobayashi J, Achiwa I, Yoda H, Tsuchiya K, Nakajima Y et al. Cardiac
34. Chen EZ, Chiu RW, Sun H, Akolekar R, Chan KC, Leung TY et al. Noninvasive
surgery in patients with trisomy 18. Pediatr Cardiol 2009;30:729-34.
prenatal diagnosis of fetal trisomy 18 and trisomy 13 by maternal plasma DNA
45. Kaneko Y, Kobayashi J, Yamamoto Y, Yoda H, Kanetaka Y, Nakajima Y et al.
sequencing. PLoS One 2011;6:e21791.
Intensive cardiac management in patients with trisomy 13 or trisomy 18. Am
35. Kagan KO, Wright D, Maiz N, Pandeva I, Nicolaides KH. Screening for trisomy
J Med Genet A 2008;146A:1372-80.
18 by maternal age, fetal nuchal translucency, free beta-human chorionic
46. Yamagishi H. Cardiovascular surgery for congenital heart disease associated
gonadotropin and pregnancy-associated plasma protein-A. Ultrasound Obstet
with trisomy 18. Gen Thorac Cardiovasc Surg 2010;58:217-9.
Gynecol 2008;32:488-92.
47. Muneuchi J, Yamanoto J, Takahashi Y, Watanabe M, Yuge T, Ohno T et
36. Viora E, Zamboni C, Mortara G, Stillavato S, Bastonero S, Errante G et al.
al. Outcomes of cardiac surgery in trisomy 18 patients. Cardiol Young
Trisomy 18: fetal ultrasound findings at different gestational ages. Am J Med
Genet A 2007;143:553-7. 2011;21:209-15.
37. Szigeti Z, Csapó Z, Joó J, Pete B, Papp Z, Papp C. Quality control of prenatal 48. Sociedade Brasileira de Pediatria [homepage on the Internet]. Programa de
sonography in detecting trisomy 18. The value of perinatal autopsy. Early Hum Reanimação Neonatal da Sociedade Brasileira de Pediatria: Condutas 2011
Dev 2007;83:505-9. [cited 2012 Dec 05]. Available from: http://www.sbp.com.br/pdfs/PRN-SBP-
38. Diniz D. Selective abortion in Brazil: the anencephaly case. Dev World Bioeth ReanimacaNeonatal-2011-24jan11.pdf
2007;7:64-7. 49. Uehara S, Yaegashi N, Maeda T, Hoshi N, Fujimoto S, Fujimori K et al. Risk of
39. Brewer CM, Holloway SH, Stone DH, Carothers AD, FitzPatrick DR. Survival in recurrence of fetal chromosomal aberrations: analysis of trisomy 21, trisomy
trisomy 13 and trisomy 18 cases ascertained from population based registers. 18, trisomy 13, and 45,X in 1,076 Japanese mothers. J Obstet Gynaecol Res
J Med Genet 2002;39:e54. 1999;25:373-9.

120
Rev Paul Pediatr 2013;31(1):111-20.