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Jurnal Embriologi 3
Jurnal Embriologi 3
43
Autosomal Trisomies
Cynthia J Curry
USCF Genetic Medicine Central California, Fresno, CA, USA
This article is a revision of the previous edition article by John L Tolmie and Una MacFadyen, volume 2, pp 10111037, 2007, Elsevier Ltd.
43.1 INTRODUCTION
It is now over 50 years since the recognition of the
chromosomal basis for trisomy 21 (T21), Down syndrome
(DS), first described clinically by the British physician John
Langdon Down in the nineteenth century. Recognition of
the other two major trisomies, trisomy 13 (T13) and trisomy 18 (T18), followed quickly after the discovery of T21
(1). Calculated live-birth rates of these conditions are 1 in
629 for T21, 1 in 6666 for T18, and 1 in 12,500 for T13
(2,3). The rates of all three autosomal trisomies increase
markedly with advancing maternal age (4,5,6) and are
lower than the rates observed in prenatal life since only
about 25% of T21 conceptions, 5% of T18 conceptions,
and 2.5% of T13 conceptions survive to birth, with most
but not all intrauterine deaths occurring in early pregnancy.
Postnatal mortality associated with T18 and T13 is
also very high, and the median survival time of infants
with these trisomies is about 10days. About 510% of
T18 and T13 infants survive to 1year of age (7,8,9).
These survival figures have not changed in recent years,
whereas T21 survival data indicate greatly improved
life expectancy. This is due primarily to the longer survival of infants with heart diseaseover 80% survival in
many centers (10,11). Survival has also increased because
of treatment of infections with antibiotics and generally
enhanced surveillance for the medical complications
of DS. This improved life expectancy has implications
for health care provision for older individuals with DS
(12,13) as well as informing decisions regarding health
maintenance and intervention in the infant and child
(14,15). In developed societies, increasing life expectancy
has been accompanied by a decreasing birth prevalence
of DS because of prenatal screening programs that offer
invasive and noninvasive prenatal diagnosis (3,16,17,18).
(a)
(b)
(c)
(d)
FIGURE 43-1 Features of Down syndrome. (a) Brushfield spots. (b) Typical hand configuration with transverse crease and fifth finger
clinodactyly. (c) Sandal gapincreased space between toes one and two (d) Typical ear, which is small (<3%) with overfolded helix.
(a)
(b)
(c)
FIGURE 43-2 The changing face of Down syndrome with age. (a) infant, (b) young child, and (c) 47-year-old adult (note hearing aid, gray
hair, edentulous).
chromosomal syndrome that has a close facial resemblance is the microdeletion of chromosome 9q34 (73).
43.3.9 Growth
At birth, infants with DS show mild growth retardation,
with mean birth weight, length, and head circumference
lying between the 10th and 15th percentiles calculated
for chromosomally normal infants (89). In a study of
105 children with DS, length, weight and head circumference were below those of typical children and remained
lower until puberty, with the growth spurt occurring earlier than in the normal population (11 in boys and 9.5
in girls) (90). Growth charts for children with DS are
available in the United States and in several other countries (9194). Successful efforts have also been reported
to produce specific growth data for use in an electronic
medical record (95).
Obesity is common in DS (96), and it is suggested that
all those over 5years with weight over 75th percentile
should have the body mass index (BMI) charted. BMI
above 98th percentile is an indication for further assessment. The majority of children with DS are obese by
age three to four (82). The prevalence of obesity in DS
Abnormalities affecting red cells, white cells and platelets are common in DS. At birth, 65% of DS infants have
polycythemia (141). Interestingly, the mouse model of
T21 demonstrates many of the same hematologic features of human DS including thrombocytosis, macrocytosis and a myeloproliferative disorder (142,143).
Neutropenia and macrocytosis are also common in DS
and the reasons are not known. Transient myeloproliferative disease (TMD) or transient leukemia almost
exclusively affects infants with DS. Recent work in
another mouse model for DS suggests that trisomy for
the gene ERG may underlie this phenotype, as reduction to disomy for ERG corrected the myeloproliferative
phenotype (144). The rate of TMD diagnosed prenatally
or postnatally is 20%.
A reported prenatal presentation of TMD is that
of generalized hydrops and is generally fatal (145)
(Figure 43-3). Most cases of TMD are asymptomatic
with resolution by 23months of age, but some have
severe disease (146,147). Presenting symptoms can
include hepatosplenomegaly, obstructive jaundice, liver
failure and ascites. Laboratory findings include leukocytosis; reduced, raised, or even normal platelet counts; and
low, high, or normal hemoglobin. TMD is characterized
by the presence of blasts in peripheral blood from a few
to >200,000L. With time the blasts decrease spontaneously. Unlike other forms of leukemia, the percentage of
blasts in bone marrow is lower than in peripheral blood.
Vesiculopapular skin findings are common, which may
be a clue to the presence of TMD, and these findings
resolve with hematological improvement (148,149).
Although spontaneous resolution in the first 3months
is usual, about 25% of affected children will, within
4years, develop myelodysplastic syndrome and acute
The risk of developing acute lymphoblastic leukemia (ALL) in DS is 1020 times higher than in control
children, accounting for 13% of children with ALL
(161). Clinical symptomatology is similar to that seen
in patients without DS. Mediastinal mass and CNS
leukemia, unfavorable signs, are less likely to occur in
patients with DS, as are T-cell leukemia and translocations 9;22 and 4;11. DS children, usually less than
10years of age, respond to chemotherapy as well
as control children with ALL. Children with DS are
more likely to experience severe toxicity with standard
chemotherapy regimens, particularly those requiring
methotrexate, and often require reduced doses of chemotherapy (162,163).
Children with DS and ALL have an increased number of deaths caused by infection, a decreased five-year
survival and more treatment-related complications as
compared to children with ALL who do not have DS
(150). These findings emphasize the need for providing
aggressive supportive care for patients with DS and ALL.
10
11
12
chromosomes are not properly attached to the spindle; spindle checkpoint proteins are being investigated
to determine if gradual decline in the efficiency of the
checkpoint explains maternal age-related probability of
aneuploidy (196,197).
As maternal age-adjusted DS rates vary little across
human populations (198), these are unlikely to be greatly
influenced by environmental factors such as periconceptional multivitamin use (199), but putative associations such as between poor socioeconomic status and
maternal meiosis II error, and between parity and DS,
have been examined (200,201). Other factors put forward that might influence nondisjunction rates include
changes in follicular development unrelated to the size of
the oocyte pool (202,203); reduced ovarian complement,
whether due to congenital absence or surgical removal
(204); and accumulation of spontaneous mitochondrial
DNA deletion mutations that diminish the supply of
energy to cells surrounding the oocyte (205). Inheritance
of methylenetetrahydrofolate reductase (MTHFR) gene
polymorphisms has been linked to chromosome 21 nondisjunction. Examination of transmission frequencies
of the MTHFR 677T and 677C alleles from heterozygous parents to children with DS revealed that the 677T
allele was transmitted to children with DS at a significantly higher rate and the 677C allele was transmitted
at a significantly lower rate (206). Most conceptions
with T21 end in pregnancy loss, and it was proposed
that preferential transmission of the 677T allele in this
population of live-born infants with DS could reflect a
survival advantage. A putative association between birth
of a child with folate-associated neural tube defect or
hydrocephalus and increased risk of T21 is controversial (207,208). A 2010 study looking at predispositon
to congenital heart disease in DS studied a group of 121
case families (mother, father, and proband with DS and
CHD) and 122 control families (mother, father, and proband with DS and no CHD); tag SNPs were genotyped
in and around five folate pathway genes: 5,10-MTHFR,
methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine beta-synthase (CBS), and
the reduced folate carrier (SLC19A1, RFC1). SLC19A1
was found to be associated with CHD using a multilocus allele-sharing test. In addition, the known functional
polymorphism MTHFR C1298A was overtransmitted to
cases with CHD and undertransmitted to controls. The
authors concluded that the disruption of the folate pathway contributes to the incidence of CHD among individuals with DS (209). In summary, altered patterns of
genetic recombination appear to be a common risk factor for T21 and for other maternal meiosis I trisomies,
but the size and direction of the alteration varies with
the chromosome involved (210). In addition, alterations
in the folate pathway genes may impact the occurrence
of congenital heart disease and possibly other defects
in DS. A chromosome-nonspecific tendency to nondisjunction may explain why there is a slight excess of
13
14
rob(14q21q) carrier, the risk of recurrence at amniocentesis is 15% (closer to 10% at term because of fetal
demise after 16weeks gestation), compared with a
much lower risk of less than 5%, even less than 1%, if
the father is the translocation carrier. In parental translocation carriers of both the 14/21 translocation and the
13/14 translocation recurrence risk data was confirmed
in a study of embryos from preimplantation genetic diagnosis (234). Although data are scanty, the same risks and
sex difference most probably apply to other heterologous
Robertsonian translocations involving chromosome 21
(rob (13q21q), rob(15q21q), and rob(21q22q).
Translocation interchange T21 is a rarer cytogenetic
variant that has been reported in more than 20 families
with reciprocal translocations involving chromosome
21q. Usually, a large chromosome (numbers 1 through
12) is involved, and there is underlying 3:1 segregation,
most often in the carrier mother, with a high risk of
recurrence (235).
43.3.22.5 Family History of Down Syndrome. When
the proband has confirmed T21, relatives other than the
probands parents may be advised that their positive
family history does not confer an appreciably increased
risk of T21, except, of course, when the family history
absolutely suggests otherwise. Gair and colleagues (236)
reported one such family with four cases of T21 in three
generations.
In the case of an affected individual with unknown
karyotype, based on the mothers age at the birth of the
proband, the probability of translocation DS is very low
when the mother is over 35years and no greater than
10% at the youngest maternal age. Therefore, chromosome analysis carried out on a parent with a positive
family history of DS rarely discloses a balanced Robertsonian translocation. Chromosome analysis may be
offered to an expectant relative with explicit understanding that a normal result does not abolish risk of
an abnormal pregnancy outcome. Aside from other
chromosomal or inherited syndromes being mistaken for
DS, cryptic or submicroscopic translocation involving
chromosome 21q may cause recurrent DS with a normal
karyotype (72).
43.4 TRISOMY 18
T18, or Edwards syndrome, was first diagnosed cytogenetically 1year after T21 (237). It is the second most
common trisomy. Neonatologists and pediatricians are
usually familiar with the characteristic presentation and
medical course of this serious trisomy.
(a)
15
(b)
FIGURE 43-4 Two infants with trisomy 18. Note triangular face, small mouth, downslanting palbebral fissures, overlapping fingers, and short
sternum.
(a)
(b)
FIGURE 43-5 Trisomy 18. (a) Overlapping fingers in fetus. Note severe nail hypoplasia. (b) Rocker bottom foot.
choroid plexus cyst is a frequent normal developmental
finding, which resolves in the third trimester, and in the
absence of other findings is unlikely to be due to T18
(55). On the other hand, large and/or multiple choroid
plexus cysts in the presence of other consistent anomalies are strongly suggestive of T18. A study by Lai and
colleagues (243) reviewed 10years experience with 69
diagnoses of T18. The detection rate of fetal anomalies by ultrasound was 93% at <14weeks and 100% at
1821weeks. A normal detailed ultrasound with normal
fetal growth and normal amniotic fluid in the midtrimester essentially rules out T18.
A definitive diagnosis of T18 by chorionic villus biopsy
or amniocentesis should prompt careful counseling of
the family, which should take into account the familys
cultural and religious beliefs. Most families receiving this
diagnosis will elect termination after considering fully
this serious handicapping condition. Some families will
want to continue the pregnancy and should be supported
in this decision (244). There should be a dialog between
the obstetric/neonatal team and the family to achieve
decisions that will be in the best interests of the child.
The practice of prenatal consultation with the family and
16
supportive counseling. Utilization of a neonatal palliative care team, if available, and use of local infant hospice
resources should be encouraged and can help families
and health care providers achieve mutual goals for the
infant and family. Even with full intervention including
surgery and ventilator support the outlook for long-term
life seems not to be improved, and these are the facts that
families should understand in their decision-making.
A clinical diagnosis should always be confirmed by a
postnatal karyotype or FISH. Array comparative genomic
hybridization (array) will also confirm this diagnosis,
but is an expensive option when the clinical diagnosis is
unambiguous. FISH and array studies can be particularly
useful on formalin fixed tissue when the infant is stillborn and/or macerated and routine karyotyping is not
successful.
17
43.5 TRISOMY 13
In 1960, Patau and coworkers (275) reported T13 syndrome in the same issue of The Lancet that contained
Edwards and colleagues description of T18. That T13
infant had an extra D-group acrocentric chromosome,
microcephaly, anophthalmia/microphthalmia, bilateral
cleft lip and palate, and polydactyly. Notably, she was still
alive at 13 months. The classic T13 syndrome phenotype
was highly distinctive and had almost certainly been the
subject of detailed case reports in earlier centuries (276).
18
(a)
(b)
FIGURE 43-6 Trisomy 13. (a) Typical face with bulbous nose and micropthalmia. Note postaxial polydactyly. (b) Typical scalp defects in trisomy 13.
of T13 can be unexpected, as when features of the Potter
sequence obscure the craniofacial findings (personal
experience).
Other pathologic findings in affected fetuses and
infants include atrial and ventricular septal defects with
patent ductus arteriosus, omphalocele, incomplete intestinal rotation or malrotation with unattached mesentery,
enlarged lobulated kidneys with cystic change in the cortex and medulla, accessory spleen, abnormal liver lobation, microscopic pancreatic dysplasia, and changes in
the morphology of the axial skeleton (280).
43.5.3 Management
Given the evident seriousness of the malformations present in most affected infants, the immediate management
of newborn infants with T13 and subsequent management of children with T13 raises ethical problems similar
to those encountered in relation to management of T18
or other seriously malformed infants and children (discussed earlier). Median survival in T13 is less than 1week
(7), and more than 80% of affected infants die during
the first month, but about 3% are alive at 6months. If
major congenital heart and renal defects are present,
surgery is usually not undertaken. The issue of cardiac
surgery may become important if the child survives to
23 months and is developing pulmonary hypertension.
One series of nine patients who underwent surgery with
trisomy 18 or 13 found that four of the nine remained
alive at age 2years (285). Individuals surviving to childhood and adulthood with T13 who do not have lifethreatening malformations have profound intellectual
impairment, severe sensory impairments, epilepsy, and
19
20
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Biography
r Cynthia Curry is a clinical geneticist, Professor of Pediatrics at UCSF San Francisco and
D
adjunct Professor of Pediatrics at Stanford. She practices in Fresno, California, where she
is director of a State of California Prenatal Diagnosis Center and Genetic Medicine Central
California. She is a graduate of Mt Holyoke College and Yale University School of Medicine.
She is trained in pediatrics at the University of Washington and the University of Minnesota.
She completed a fellowship in clinical genetics at UCSF. She has served on the American Board
of Medical Genetics and on the board of the American Society of Human Genetics. Her research
interests include microarray abnormalities, skeletal dysplasias and syndrome delineation.