Autosomal trisomies

Dr Catana Andreea

Down Syndrome Trisomy 21

most frequent chromosome disorder incidence 1:650-1:800 new born

real incidence of embryos with trisomy 21 is (1:200), about are eliminated (AB)
More frequent in males (sex ratio 3:2)

Etiopathology
Cause: trisomy of 21q22 region, genes found in this region express themselves by a dosage effect characteristic clinical phenotype Chromosome non-disjunction during maternal meiosis, associated to advanced maternal age

Down Syndrome trisomy 21

95% of pacients have 3 different copies of cchromosome 21 homogenous trisomy 21

4% of patients have trisomy 21 because of a translocation involving chromosome 21 Robertsonian translocation

1% of pacients have mosaicism ( a trisomic cellular line and a normal diploid cellular line postzigotic event) -

 Down Syndrome Critical Region. However, this region is not one small isolated spot, but most likely several areas that are not necessarily side by side. The 21st chromosome may actually hold 200 to 250 genes (being the smallest chromosome in the body in terms of total number of genes); but it's estimated that only a small percentage of those may eventually be involved in producing the features of Down syndrome.

Phenotype (symptoms)
muscular hypotonia, articular hiperlaxity and nervous hiporeflexia Small, rounded cranium (brahicefalia), flattened occiput, large fontanelas facial profile is flattened because of facial bones hypoplasia . palpebral slots are oblique, epicantus Eye anomalies ( convergent strabismus, blefarites, nistagmus) I Brushfield spots, in the iris) Small, rounded, dysplastic, low inserted ears. Deafness (50%) Small mouth with lingual protrusion High, narrow arch palate.

 Small, short hands with brachidactilia or clinodactilia of the 5 th finger Simian crease (single palmary crease) Dysplastic pelvis, extreme joint elasticity

 Mental retardation can vary from medium to severe ( maximum level of acknowledge of a 6-8 old child)
Delayed, incomplete pubertary development, sterility

Congenital abnormalities
Congenital heart malformalities , 30-40% have atrioventricular septal defect digestive abnormalities duodenal, ombilical hernia and ring pancreas SNC anomalies

Evolutionon/ prognosis
Life expectancy 40-60 years

Associated pathology >high risk to develop cancer, especially leukemia >high risk to develop infections (immunologic anomalies) >late onset/absent puberty >psychological/psychiatric pathology

Nuchal edema

Prenatal diagnosis

CVS (9-12 w)
AB risk (2%), infection,
hemorrhage, limb anomalies | Amniocentesis (14-20 w) AB risk (0,5%), hemorrhage, infection | amniocyte culture | Karyotype

Maternal seerum screening

Orientative tests NOT diagnostic ! The link between the low level of maternal seerum of AFP and trisomy 21 was demonstrated for the first time 1984 by Merkatz & col. Pregnancies with fetuses with Down syndrome associate :

>low level of alphafetoprotein (AFP)

>increased level of human corionic gonadotrofin (-HCG ) >low level of unconjugated estriol ( uE3)

Triple test

> amniocentesis at a risk> 1/250 > 70% accurate, 5%false positive results

Prenatal diagnosis molecular cytological diagnosis - FISH

Genetic counseling
Genetic counseling recommended:
>women > 35 ani
>positive history of trisomy 21 >Couple with balanced chromosomal abnormalities >Spontaneous AB, dead fetuses >IVF

Recurrence risk:

Homogenous trismomy 21 1% (according to the mother age) Trisomy 21 with Robertsonian translocation from 10% (nonhomologous acrocentric chromosomes) to 100% (t 21/21) Trisomy 21 in mosaic - < 0,1%

 AFP is produced in the yolk sac and fetal liver. Unconjugated estriol and hCG are produced by the placenta. The maternal serum levels of each of these proteins and of steroid hormones vary with the gestational age of the pregnancy. With trisomy 21, second-trimester maternal serum levels of AFP and unconjugated estriol are about 25 percent lower than normal levels maternal serum hCG is approximately two times higher than the normal hCG level The triple test can detect approximately 60 percent of the pregnancies affected by trisomy 21, with a false-positive rate of about 5 percent. In women older than 35 years, the triple test fails to detect 10 to 15 percent of pregnancies affected by trisomy 21.

Trisomy 13 Patau Syndrome

Trisomy 13 is a rare, severe chromosomal disorder characterisated by the presence of an extra 13 chromosome (47XY+13 or 47XX+13). Plurimalformative severe syndrome Majoritaty of embryos with trisomy 13 are aborted spontaneousely from the first semester of pregnancy

 Patau syndrome is the consequence of trisomy 13. The extra 13 chromosome is the result of chromosome nondisjunction from meiosis I (ussualy maternal) The presence of a balanced translocation in the parents it is also considered a risk factor to have a child with trisomy 13.

Simptoms
Low birth wheight Microcephaly, large, opened sutures,scalp defects, flat forehead Microftalmia/anoftalmia, ciclopia, irian coloboma, cataracts, retinian dysplaisa labiopalatoschisis (clef palate and lip) malformated, low implanted ears

 SNC abnormalities: unique ventricle, calos body agenesia, Holoprozencephalia (holoprozencefalon 2 cerebral hemispheres simetrical developement of facial and SNC organs) Genes PAX 2 (), PAX6 ()

 Cardiac abnormalities(ventricular sept defect, common arterial trunk, etc) Policistic kidney Bifid uterus, Criptorchidia, hipospadias Hemangioamas MENTAL RETARDATION

Diagnosis
Clinical diagnosis is sugested by the characteristic triad : cleft palate and lip, microftalmia/anoftalmia and postaxial polidactily (70% of cases). Confirmation of diagnosis implies citogenetic methods (karyotype).

Prenatal Diagnosis
Fetal ultrasoundin the firt and second trimester of pregnancy can identify the majority of fetal abnormalities characteristic for trisomy 13 Maternal seerum screening from the firt trimester of pregnancy (beta hCG si a PAAP-A) and also in the second trimester of pregnancy (the triple test) Prenatal certeinety iagnosis requires corionic vilus sampling (trimester I) or amniocentesis (trimester II ) both folowed by chromosome analysis.

Genetic counceling
Reccurence risk is very low in case of homogenous trisomy 13 of trisomy 13 with mosaicism (0,5%). In case of trisomy 13 due to an balanced translocation present in one of the parents the reccurence risk in much higher, as for a Robertsonian translocatioin it is around 10% or even 100% in case of reciprocal 13-13 robertsonian translocation .

Trisomy 18 Edwards Syndrome

Trisomy 18 is a rare chromosomal disorder (incidence around 1:8000nn), very severe characterisated by a plurimalformative syndrome due to the presence of an extra 18 chromosome. 95% of all embryos with trisomy 18 are spontaneoulesly aborted spontan in the first 2 trimesters of pregnancy.

80% of all cases are present in female embryos

Causes
Edwards syndrome is produced by trisomy 18, the presence of the extra 18 chromosome is the consequence of a cellular meiotic accident (chromosome- chromatide nondisjunction), that takes place more freqoently in the maternal gametogenesis, advanced maternal age beeing one of the most important risk factor related to this chromosome abnormality.

Simptoms
Low birth weight, generalisated muscle hypertonia and characteristic cranio-facial dismorphia.

 Muscle hypertonia with the specific contracture of hand muscles (digists 2 and 5 are flectated and cover digits 3 and 4= clenched), halux in dorsiflexia

Neonatal period: Low birth weight (according to gestational period) Long head (dolicocephaly), small head (microcephly) with proeminent occiput and flattened forehead Small chin (micrognatia) Low implanted, hypoplastic ears Abnormal dermatogliph pattern (exces of arches, simian crease) Severe metal retardation

Severe congenital abnormalities:

cardiac (90% of cases), renal (horseshoe like kidney), cerebral, vetebral intestinal (piloric stenosis, diafragmatic opening). Cleft lip and palate (labiopalatoschisis) with deglution abnormalities

Diagnosis
Trisomy 18 is quite easely suspicioned on the basis of the specific clinical abnormalities present at the time of birth. The certenty diagnosis also needs the specific citogenetic evaluation (karyotype with an extra 18 chromosome).

Prenatal diagnosis First trimester ultrasound can identify the nuchal edema The morphologic ultrasound from the II triomester could identify intrauterine growth failure, cardiac abnormalities, neural tube defects, etc Maternal seerum screening - the double test ( Beta hCG si PAPP-A) - the modified triple test with low levels of, alfafetoprotein (AFP), unconjugated estriol (uE3) and corionic human gonadotrophin (hCG) The specific diagnosis requires corionic vilus biopsy (first trimester) or amniocentesis (second trimester), also folowed by fetal chromosome analysis.

Genetic

counseling

Estimated risk of recurrency of trisomy18 is very small,about 0,5-1%, for complete, homogenous trisomy18.
In case of partial trisomy, much more rare, the reccurence risk depends on the absence or respectively the absence of translocation in the parents.