SASUOG

South African Society for Ultrasound
in Obstetrics and Gynaecology

TEACHINGS / LECTURES / CASES


How long should an anomaly scan take?

Choroid plexus cysts an ultrasound marker for chromosomal anomalies

 

41 year old lady

G3P2

Two previous term uncomplicated pregnancies.

Referred from ANC to the ultrasound department @ 20 weeks for a routine anomaly scan in pregnancy and counseling for age related risk of chromosomal anomalies and the option of fetal karyotyping.


Sonar demonstrated a singleton viable intrauterine pregnancy with no structural fetal anomalies however bilateral choroid plexus cysts were noted.


The patient was counseled about this finding including her age related risk for chromosomal anomalies and in particular trisomy 18.

The patient opted to have fetal karyotyping and an uncomplicated amniocentesis was performed.  


Fetal karyotype was found to be 47XX + 18   (Trisomy 18 female fetus).

The patient was counseled about this finding and opted for a termination of pregnancy.


 

Trisomy:

An extra chromosome in each cell in this case an extra copy of chromosome 18 this can be a complete extra chromosome or part thereof.

Most autosomal trisomies are non viable, except for trisomies 13,18,and 21.
Trisomy 18 (Edward syndrome)

This condition was first recognized as a specific entity in 1960 by discovery of the extra 18 chromosome in neonates with a particular pattern of malformation (Edwards, Patau, Smith et. al)

Characterised by malformations of multiple organ systems, it is the second most common multiple malformation syndrome with an incidence of about of 3/10 000 live births.

There is a 3:1 preponderance females to males.

 


Etiology:

Classic complete aneuploidy (3x chromosome 18) is believed to be the result of non- disjunction at meiosis in the majority of cases.


Maternal meiosis: 

85-90%  

meisois 1 (75%); meiosis 2 (25%)

Mitotic:

3-5%

Paternal meiosis: 

3-5%

Translocations:

4%        Robertsonian

de nuovo75%; familial 25%

Other:  

1%


 

In practically all cases, non-disjunction occurs at random, with no recognizable individual predisposition. The great majority have complete trisomy 18, the etiology is faulty chromosomal distribution, which is more likely to occur at older maternal age, the mean maternal age at birth of babies with this syndrome is 32 years.

Non-disjunction can happen at any maternal age, but is more common in older mothers.    

 


Finally,a small fraction of apparent complete aneuploidy may be due to early miotic non-disjunction in a 46 N conceptus with loss (or restriction to extra embryonic- tissue) of the normal cell line.

If non disjunction occurs during mitosis in the developing embryo, mosaicism results, wherein the embryo consists of trisomic and normal cells ( again the monosomic cells usually die, except for the monosomy X line).

Mosaicism for an additional chromosome 18 will lead to a partial clinical expression of the pattern of T18 with longer survival and any degree of variation between quasi normal and the full pattern.


Alternatively, where an abnormality has arisen in a pre-miotic gametocyte, with the parent thus having a segment of gonad that carries the abnormality referred to as gonadal moscaicism. Such parents are at increased risk for only one karyotypic defect. 

Changes of chromosome structure can involve single chromosomes or an exchange of material between chromosomes.


Translocation cases, the result of chromosomal breakages, can only be excluded by chromosomal studies.

When such a case is found parents should also have karyotyping and chromosomal studies to determine if one of them carries a balance translocation with a high risk of recurrence in a future offspring.

A piece of a chromosome may be lost by deletion or may be duplicated. Deletion results in monosomy for a group of genes, and duplication in trisomy for the genes.

Chromosome segments can also be inverted – (180 degrees flip) from their normal orientation. Where no genetic material is gained or lost, these changes will probably have no  phenotypic and clinical impact.


Rarely a gene may be disrupted by the chromosome breakage involved in the inversion, but there are vast areas of genetically inserted material between gene groups, so usually these breaks cause no phenotypic or clinical consequence.

Such breaks can lead to unbalanced chromosomes after crossing over in meiosis.


Partial trisomy 18:

Trisomy of the short arm of 18 causes a very non specific, mild clinical picture with little or no mental deficiency.


In the case of familial trisomy 18 the short arm, centromere and proximal 1/3 of the long arm show features of   trisomy 18.

Trisomy of the whole longarm   is clinically indistinguishable from the full T18 syndrome.

Trisomy for the distal 1/3 to ½ of the long arm leads to a partial picture of T18 with longer survival and less and profound mental retardation. In infancy and early childhood these children resemble T18 cases, whereas teenagers and adults display a more non-specific pattern of malformation. 


Although no adequate studies of recurrence risk exist for full trisomy 18 cases, it seems safe to presume that the recurrence risk would be even lower than the 1% for full trisomy 21 syndrome cases. The latter statement is predicated on the indication that most T18 individuals die in the embryonic or fetal life as suggested by the chromosomal findings in spontaneous abortuses.


The risk of trisomies in women who have had a previous fetus or child with a trisomy is higher than the one expected on the basis of their age alone, and about 0.75% higher than maternal and gestational age risk for the trisomy at the time of testing.


The reason for this increased risk is that a small portion (<5%) of couples with a previously affected pregnancy have a mosaicism or a genetic defect that interferes with the normal process of dysjunction,in this group the risk of recurrence is significant.In the majority of couples (>95%) the risk of recurrence is actually not increased.

Curent evidence however suggests that recurrence is chromosome specific and thus in the majority of cases the likely mechanism is parental mosaicism.


Clinical features of Trisomy 18 or Edwards Syndrome:

50% or more of patients have:

General:

Reduced fetal movements, 30% premature, 30% postmature.

Polyhydramnios, small placenta, 2 vessel cords, IUGR, mean EBW 2340g.

Feeble and weak crying efforts, poor apgars episodes of neonatal apnoea, hypoplasia of skeletal muscle, subcutaneous and adipose tissue.

Mental handicap, hypertonicity (after the neonatal period). Diminished response to sound.


Head and Face:

Prominent occiput, bifrontal diameter is narrow.

Malformed, low set auricles.

Palpebral fissures are short. Small oral orifice, narrow palatal arch.

Micrognathia.


Extremities:

Clenched hands, overlapping fingers (index finger over the 3rd,and  5th over 4th.)

Absent crease on distal part of 5th finger with or without distal creases on 3rd and 4th fingers.

A low arch dermal ridge configuration on six or more fingertips.

Hypoplastic nails, particularly of 5th finger and toes. Short and frequently dorsi-flexed hallux.


Thorax:

Sernum is short with reduced number of ossification centrae.

Nipples are small.


Abdominal Wall:

Hernias of inguinal or umbilical and/or rectal muscle disatasis.


Pelvis and Hips:

A small pelvis, with limited hip abduction


Genitalia:

Cryptorchidism in males


Skin:

Redundant, mild hirsutism or forehead and back.


Cardiac:

VSD, auricular septal defects, patent ducuts arteriosis.


Abnormalities found less commonly:


Central nervous system:

Facial palsy, myelinisation paucicity, microgyria, defect of corpus callosum, cerebellar hypoplasia, hydrochephalus, meningomyelocoele.


Head and Face:

Wide fontanelles, microcephaly, hypoplasia of orbital ridges.

Ptotic eye lids, inner epicanthal folds, corneal opacities.

Cleft lip and/or palate.

Cranial bones appear wormian, shallow elongated sella turcica.

Slanted palpebral fissures,  hypertelorism,cataracts, colobomata of iris ,micropthalmos, choanal atresia.,


Hands and feet:

Ulnar or radial deviation of hand.

Hypoplastic to absent thumb, simian crease.

Rockerbottom feet, Talipes equinovares, syndactyly of 2nd and 3rd toes.

Syndactlyly of 3rd and 4th  fingers, polydactly, short 5th metacarpals, ecterodactyly.


Thorax:

Appears broad, with or without widely spaced nipples.


Other skeletal:

Radial aplasia.

Incomplete ossification of clavicle.

Fused vertebrae, he mivertebrae, shortneck, scoliosis, rib anomalies, pectus excavatum, dislocated hip.


Pelvis and Hips:

Dislocated hip.


Genitalia:

Female: hypoplasia of labia majora with prominent clitoris

Anus is malposed or funnel-shaped 

Male: Hypospadias, bifid scrotum.

Femal Bifid uterus, ovarian hypoplasia. 


Cardiac:

Bicuspid aortic and/or pulmonic valves, nodularity of valve leaflets, pulmonic stenosis, coarcation of aorta.

Transposition of the great vessels, Tetrallogy of Fallots, Co-arcation of the aorta, coronary artery anomalies, dextrocardia,abberant subclavian atery, intimal proliferation in arteries with atherosclerotic changes and medial calcification.

Lung:

Malsegmentation to absence of right lung


Diaphragm:

Diaphragmatic hernia (muscle hypoplasia with or without eventration).


Abdomen:

Meckels diverticulum, heterotopic pancreatic and/or splenic tissue, Omphalocoele(exomphalos). Colon :incomplete rotation.

Pyloric stenosis, extrahepatic billiary atrasia, hypoplastic gallbladder, gallstones, imperforate anus


Renal:

Horshoe kidney, ectopic kidney, double ureter, 

Hydronephrosis,polycystic kidneys(small cysts).

Wilms tumor.


Endocrine:

Thyroid or adrenal hypoplasia

Other

Haemangiomata, thymic hypoplasia, trageoesophageal fistulae, thrombocytopenia.


Prenatal:

50 – 70% of trisomic fetuses will be lost as in the first trimester due to the intrauterine lethality of the condition.

Trisomic fetusses can demonstrate reduced fetal movements.

There is an increased risk for preterm delivery about1/3 and postdates also about 1/3 pregnancies.

SGA is often severe and symmetrical is a common finding and often these pregnancies develop polyhydramnios.

Neonates with T18 syndrome are usually born with poor apgars necessitating resucutation at birth, with apnoeic episodes in the neonatal period. These babies are usual feeble and have a limited capacity for survival.


Poor sucking ability often requires nasogastric tube feeding, but even with optimal management they fail to thrive.

There is a 50% mortality in the first week of life, of the survivors the majority die in the next 12 months.

Only 5 – 10% survive in the first year of life and are severely mentally handicapped.

Most children who survive the first year are unable to walk in an unassisted manner and verbal communication is usually limited to a few single words.

One must realize however that some older children with trisomy 18 do smile, laugh and interact with their families.

All these children do achieve some psychomotor maturation and continue to learn.

There are some reports of T18 children surviving to beyond 10 years.


Common Ultrasound findings in trisomy 18 fetusses:

Strawberry shaped head

Brachicephaly

Ventriculomegaly

Choroid Plexux cysts

Absent Corpus callosum

Posterior fossa cyst

Enlarged cysterna magna

Facial cleft

Micrognathia

Nuchal edema

Diaphragmatic hernia

Cardiac abnormality

Exomphalos (omphalocoele)

Collapsed stomach

Mild hydronephrosis

Other renal abnormalities

SGA

Relatively short femur

Overlapping fingers

Talipes (clubfeet)


Other ultrasonographically detectable anomalies:

Low set ears

Micropthalmos

Hypertelorism

Short radial ray

Rockerbottom foot

Cryptorchidism

2 Vessel Cord

Polyhydramnios

Occasional:

Meningomyelocoele


Major differential diagnosis:

Freeman – Sheldon Syndrome

Pena Shokeir syndrome

Smith-Lemli Optiz syndrome

Triploidy

Trisomy 9


Ultrasound diagnosis:

First trimester 11-14 weeks:

Increased nuchal translucency

Abnormal first trimester biochemistry


Routine 18 – 23 weeks anomaly scan:

80% of fetuses with T18 are detectable by features in the second trimester as listed above.

This may be found on routine scan or where detail scanning is done for “screen positive” second trimester biochemistry or on the history of other high risk factors such as advanced maternal age or history of a previously chromosomally abnormal pregnancy or child.


Although trisomy 18 occurs in 1/100 fetuses with choroid plexus cysts, where the CPC are an isolated finding the risk of the fetus having trisomy 18 falls below 1/400.

Documenting an open hand is very useful as most babies with T18 keep their hands clenched.

Many fetuses with T18 die in utero due to the intrauterine lethality of the condition. Of those liveborn 90% die in the first year of life


The 10% survivors are profoundly mentally handicapped.

CPC are found in 1-2% of pregnancies and are usually of no pathological significance.

The choroid plexus is particularly active 16 – 24 weeks of fetal life. Choroid plexus cysts all resolve spontaneously.

When other defects are present there is a high risk of chromosomal defects usually T18 but sometimes T21.

For isolated choroids plexus cysts the risk for T18 and T21 is about 1.5 x (more than) the background (existing risk by age) risk


The pearl

Choroid plexus cysts (>= 2mm) are found during 1-2% of routine anomaly scans between 18 – 23 weeks of gestation some databases include them as markers from 16 weeks.

This is irrespective of their quantity or laterality. It’s their presence that is significant.

The vast majority of isolated cysts are of no pathological significance and will resolve by about 26 weeks of gestation in 90% of cases.


Isolated CPC are considered an ultrasound marker for chromosomal anomalies particularly T18 and possiblyT21 and will increase the background risk of trisomy 18 and 21 by 1.5 X.

In their presence a meticulous and detailed scan should be performed to investigate for the presence of other ultrasound markers as listed above.

 

Patients should be counseled about this finding and where their risk (background / age risk x 1.5) exceeds 1/300 or in the case of other compounding or risk factors (other markers or fetal anomalies, advanced maternal age, positive serum screening, history of trisomic pregnancy or child) should be offered the option of fetal karyotping.

Most fetal medicine specialist units do not offer follow up scans to track their resolution. 

This case provided by:

Coronation Hospital Ultrasound Department

Coronationville

Johannesburg

Gauteng

Tel: 011 - 470 9050

Principle Sonographer: Lucille Israel

Senior Sonographers: Maki Tseki, Winnie Steenkamp

Sonographer Students: Wits Technikon

Fetal Medicine Research Fellow: Dr Ilse Erasmus

Fetal Medicine Research Midwife: SR B Calvert

Secretary: Mirriam Ravioli



References:

Diploma in Fetal Medicine Series

Diagnosis of fetal abnormalities

11-14 week scan

KH Nicolaides, NJ Sebire, RJM Snijders

Parthenon Publishing

Diploma in Fetal Medicine Series

 

Diagnosis of fetal abnormalities

The 18 – 24 week scan

G Pilu & KH Nicolaides

Parthenon Publishing

 

Ultrasound of fetal syndromes

Benaceraf

Churchill Livingstone1998

 

Chromosome Abnormalities and Genetic Counseling

R.J. McKinlay Gardner

Grant R Sutherland

Oxford University Press 1996

 

Smith’s Recognizable  patterns of Human Malformation

Saunders 5th Edition

 

Human Genetics

Bruce R Korf

Blackwell Science 1996

 

Clinical Genetics

A case-based approach

D Bonthhron, D Fitzpatrick, M Porteous & A Trainer

W.B Saunders 1998