Patterns of Fetal Anomalies

Fetal anomaly incidence:

• major anomly 3/100 births

• 10-15% = minor birth defect

• Testing for genetic disorders prior to birth can prepare families for life with a special needs child or allow parents to choose to terminate the pregnancy

Aneuploidy

abnormal number of chromosomes

Karyotype

the chromosomal complement of an individual, including the number of chromosomes and any abnormality

Trisomy

the presence of three chromosomes of a given number, rather than two

Autosomal Recessive

• a genetic condition that only appears in individuals that received two copies of an autosomal gene

  • One copy from each parent

• The gene is an an autosome, a non-sex chromosome

• Parents are carriers who have only on copy of the gene and do not exhibit the trait

What are the statistics if both parents are carriers of an autosomal recessive gene?

• there is a 25% chance of a child inheriting both abnormal genes + developing the disease

• There’s a 50% chance of a child inheriting only one abnormal gene and being a carrier

• And 25% chance the child will inherit both normal genes

Autosomal Dominant

• an affected individual has one copy of an abnormal gene on are pair of autosomal chromosomes

• Individuals w/ autosomal dominant diseases have a 50/50 chance of passing the mutant gene + the disorder onto each of their children

X-Linked

• X-linked diseases are single gene disorders that reflect the presence of defective genes on the X chromosome

Affected males do not transmit the disorder to their sons, but all of their daughters will be carriers

Mosaicism

• the occurrence of a gene mutation or chromosomal abnormality in only a portion of an individual’s cells

• This causes two different genotypes (karyotypes) in an individual

Normal Karyotype

• normal Karyotype consists of 46 chromosomes

  • 22 pairs of autosomes

  • 1 pair of sex chromosomes

    • Females XX

    • Males XY

Trisomy 13 AKA:

Patau Syndrome

Trisomy 13

• mean survival age is 2.5 days

• cardiac defects (>80%)

• IUGR

• Cleft lip / plate

• Ocular (eye) anomalies

• Clenched hands

Patau Syndrome (T13) is associated with:

• microcephaly, CNS abnormalities (ex: absent corpus callosum), abnormal posterior fossa, venticulomegaly

• Cardiac defects (>80%)

• IUGR

• Cleft lip / palate (60-70%)

• Ocular anomalies

• Rocker bottom / club feet

• Clenched hands w/ overlapping digits / polydactyly

• Abnormal features seem w/ holoprosencephaly

T13 findings:

• U/S is very sensitive for detecting Trisomy 13

  • sensitivity up to 90%

• Survivors have:

  • severe intellectual disabilities

  • seizures

  • apnea

  • feeding difficulties

  • failure to thrive

Trisomy 18 AKA:

Edwards Syndrome

Trisomy 18

• 95% result on spontaneous Ab

• Second most common autosomal trisomy

• Common intrauterine demise

Edward’s Syndrome (T18) signature finds:

• 2VC

• Cardiac anomalies (90%)

• Strawberry shaped skull**

• Cleft lip / palate

• Rocker bottom feet

• Umbilical cord cysts

Other T18 findings include:

• FGR

• Polyhydramnios

• Dolichoceohaly

• Microcephaly

• Hydrocephalus

• Agenesis of the corpus callosum

• Cerebellar hypoplasia

• Low set ears

• Micrognathia

• Clenched hands

• Club feet

• Omphalocele

• VACTERAL (S)

• Cystic hygroma

• NTD

Trisomy 21 AKA:

Down Syndrome

Trisomy 21

• most common autosomal trisomy

• 1/800 children

• High level of mortality in the first year d/t heart defects + increased incidence of leukemia

Down Syndrome (T21) signature findings:

• thick nuchal skin fold

• small / absent nasal bone

• hypoplasia midphalynx of the fifth digit

• sandal (toe) gap

• cardiac defects (A-V Canal, ASD, VSD,Tetralogy of Fallot)

• Intecardiac echigenic focus

• Duodenal atresia

• Echogenic bowel

Other T21 findings include:

• short stature

• small flat nose

• small ears

• clinodactyly

• simian crease

• brachycephaly

• flat occipital

• epicanthal folds

• protruding tongue

• cystic hygroma

• FGR

• mild ventriculomegaly

Turner Syndome AKA’s:

• monosomy

• Monosomy X

• Congenital Ovarian Hypoplasia Syndrome

Turner Syndrome

• absence of one X chromosome

• only occurs in females

• cystic hygroma

• webbed neck

• poor hearing

Monosomy findings include:

• cystic hygroma

• cardiac anomalies

  • aortic coarctation

• lymphedema

• hydrops

• renal anomalies

• short stature

• lack of sex organ development

• webbed neck

• poor hearing

Apert Syndrome

• autosomal dominant

• characterized by premature fusion of he skull bones

• craniosynostosis

• no specific maternal serum markers

  • may have elevated MSAFP in case of open spinal defect

craniosynostosis

• main characteristic of Apert Syndrome

• results in changes of head and face shape

Key characteristics of Apert Syndrome include:

• craniosynostosis

• increased cephalic index

• sinking of the midface

• maxillary underdevelopment

Other findings of Apert Syndrome include:

• frontal bossing

• premature skull fusion

• hypertelorism

• agenesis of the corpus callosum

• ventriculomegaly

• syndactyly / digit fusion

CHARGE Syndrome

• colobomatous malformation

• males

• coloboma - hole in a structure of the eye

  • affects eyesight depending on location

  • eyes may be small, + possibly also the nasal passages

Signature findings of charge syndrome:

• colobomatous malformation → hole in eye(s)

• Heart defects**

• cranial nerve anomalies (degree of hearing loss)

• ear anomalies (anomalies of shape + size almost always occur)

• Atresia Choanae

Other CHARGE syndrome findings may include:

• Intellectual + growth deficiencies / disabilities

• Genitalia hypoplasia

• Cranial nerve anomalies

  • Swallowing difficulties, facial paralysis, diminished smell

  • Micrognathia

  • Cleft palate

  • Renal anomalies

  • Omphalocele

  • TE fistula

  • hemivertebrae

  • Hypertelorism

CHARGE syndrome cardiac anomalies:

• most commonly recognized prenatal finding w/ CHARGE

  • Tetralogy of Fallot

  • Double-Outlet RV w/ an A-V canal

  • VSD / ASD

  • Right sided + interrupted Ao arch

Goldenhar Syndrome AKA:

Oculoauriculovertebral Syndrome

Goldenhar Syndrome

• male

• Incomplete development of the ear, nose, soft palate, lip, and mandible on only one side of the body

  • Usually unilateral

  • Associated w/:

    • Scoliosis, hemivertebrae, + cervical fusion

Key findings of Oculoauriculovertebral syndrome (Goldenhar syndrome):

• facial asymmetry

• Cleft lip / palate

• Microphthalmia

• Hemivertebrae

• Scoliosis

• Respiratory + feeding problems

• Intellectual disabilities

Other findings of Goldenharr Syndrome:

• Cardiac defects → VSD’s, tetralogy of Fallot, + Aortic Coarctation

• Renal anomalies

• UPJ obstruction, Multicystic dysplastic kidney

Meckel-Gruber Syndrome

• rare

• Autosomal recessive

• Slightly more common in Finland

• Renal dysplasia, limb anomalies, + encephalocele

• Poor prognosis d/t kidney issues & oligohydramnios impacting lungs

Most common findings of Meckel-Gruber Syndrome:

• Polycystic kidney disease (100%)

• Polydactyly (55-75%)

• Occipital encephalocele (60-80%)

• Poor prognosis

Other findings of Meckel-Gruber Syndrome include:

• oligohydramnios

• Postaxial polydactyly

• Limb bowing / shortening

• Dandy-Walker Syndrome

Noonan Syndrome

• cystic hygroma is a similar finding to Turner syndrome

• Cardiac anomalies (60%)

• Low set ears, depressed nasal bridge, & macrocephaly

VACTERAL(S) Association:

• V - Vertebral anomalies

• A - Anal Atresia

• C - Cardiac anomalies

• TE - Transesophageal Fistula

• R - Renal Anomalies

• L - Limb defect

• S - Single Umbilicl Artery

• ** rare but has been associated w/ diabetic mothers

Chorionic Villus Sampling (CVS)

• biopsy of placenta or chorionic villi

• Chorionic villi are fetal in origin = ability to detect chromosome anomaly (Does not test for NTD’s!)

• Biochemical, metabolic disorders, thalassemia, sickle-cell disease may also be diagnosed

Transceevical / Transabdominal CVS approach:

• determine placental location relative to the cervix and path of sampling catheter

• Determine fetal age, lie, + viability

• Uterine mass or other obstacle?

• Risk of loss = 0.5-1.0%

• Inc risk of limb defects if performed before 8 weeks!

Transvaginal CVS approach:

• careful OB/GYN hx taken

  • Active infection of vagina / genital tract, IUD’s, & cervical stenosis are all contraindications

• Complete U/S eval

  • Confirm viability, GA, placenta location

• Pt in lithotomy position

  • Speculum inserted

Transvaginal CVS approach:

• thickest part of trophoblast (chorion frondosum) is the target area of obtaining samples

• Specimen aspirated

  • Done under constant U/S visualization

Transvaginal CVS approach sampling process:

• 20-30 mg of tissue is obtained and put in tube w/ culture medium

• Specimen is shaken and examined under light to make sure enough chorionic villi is present

  • May use microscope

• Check fetal heartbeat

The difference in the transabdominal CVS approach:

• pt is sound

• Placental thickness measured

• Abdomen site with cleansed

• Needle inserted into placenta

Transabdominal vs Transvaginal CVS:

• TA reduced risk of infection

  • Greater risk in obtaining specimen

  • Used with anterior placenta

• TV expediences more complications such as fluid leakage and vaginal spotting

  • Higher association w/ pregnancy loss

CVS advantages:

• performed early 10-12 weeks

• Results within 1 week

• Early results = options for parents

Amnio

• performed after 14 weeks

• Results take 7-14 days to grow chromosomes

Amniocentesis

• relieve polyhydramnios, predict Rh isoimmunization, detect fetal lung maturity and chromosome analysis

• Best for genetic analysis between 15-28 weeks can be done as early as 12 weeks

  • But may lead to complications

What are the indications for an amniocentesis?

• abnormality on U/S

• Screening d/t maternal disease

• Risk factor

Amniocentesis screens for:

• Gestational age

• Defects

• Placental location

• Fetal lie

• Always confirm post tap FHR!

Amniocentesis Protocol:

• Operative site is draped with sterile towel

  • Use sterile precautions entire time

    • Reduce risk of infection

  • Cover trdx with sterile cover

  • Needle inserted under U/S guidance

    • 20-30ml is withdrawn

    • Needle withdrawn

  • Check for heart rate and document

Maturity Amniocentesis

• perform anytime to determine lung Maturity for delivery

  • Usually in 3rd trimester

  • L/S ratio (Lecithin / sphingomyelin)

  • Obtain results the same day

FISH

• Fluorescence In Situ Hybridization

• Fast form of an amnio

• Results within 24 hours

• Still need to do complete amniocentesis

• Usually screens T13, 18 & 21

Cordocentesis AKA:

PUBS → Percutaneous Umbilical Blood Sampling

Cordocentesis (PUBS)

• high risk for complications

• Fetal blood sample is obtained thru needle aspiration of the umbilical cord

• Can also transfuse blood or supple medication directly to the fetus via the cord

Embryoscopy

• direct viewing of developing fetus via transcervical endoscope inserted into the extra-coelomic space in the 1st semester

• Detect fetal anomalies

• Take blood samples

• In future potential for gene therapy?