Diagnostic ultrasound ( PDFDrive )

1386 PART IV Obstetric and Fetal Sonography
Prenatal diagnosis of monogenic disorders presenting with
ultrasound abnormalities traditionally required invasive procedures
such as chorionic villus sampling or amniocentesis for
obtaining fetal cells and DNA. More recently the noninvasive
approach of genetic analysis using circulating cell-free fetal DNA
has been utilized as an aid to sonographic prenatal diagnosis of
fetal skeletal dysplasia, thus eliminating the risk of fetal loss
associated with invasive testing.
Genetic defects have been identiied in approximately 70%
of the more than 436 skeletal dysplasias. 6 Cell-free fetal DNA
testing allows for testing an early point in the pregnancy, prior
to ultrasound diagnosis, and thus may be appropriate for a fetus
known to be at risk for having skeletal dysplasia because of an
afected parent (for autosomal dominant conditions), a carrier
mother (for an X-linked condition), or parents identiied as being
carriers of an autosomal recessive skeletal dysplasia (due to a
personal or family history of an afected child or fetus). Finding
the diagnosis is important not only for providing early prenatal
diagnosis (before diagnostic indings are seen on ultrasound)
but also for preimplantation diagnosis in at-risk families.
If both parents are afected (either with the same or a difering
autosomal dominant skeletal disorder), the fetus is at 25% risk
of inheriting both conditions and this generally causes a more
severe skeletal dysplasia and is frequently lethal. In cases where
the mutation status of the parents is known, a molecular diagnosis
can distinguish between a fetus that has inherited neither dysplasia,
one dysplasia, or both.
If the risk of an afected fetus is relatively low, as when only
one parent has an autosomal recessive skeletal dysplasia or each
of the parents is afected with a diferent type of autosomal
recessive skeletal dysplasia, the appropriateness of molecular
diagnosis is less clear. For couples with a previously afected
fetus with a de novo dominant disorder, the recurrence risk is
probably less than 1% (due to gonadal mosaicism). Nevertheless,
prenatal diagnosis should be discussed and performed if the
woman or couple requests it.
When the diagnosis remains unknown, the involvement of
specialists in skeletal dysplasias may be helpful in determining
the diagnosis. It is crucial to obtain postnatal radiographs,
fetal or newborn DNA, and ibroblast culture to try and delineate
the diagnosis, the causative gene, and gene mutation. his may
help in preimplantation or prenatal diagnosis in future
pregnancies.
LETHAL SKELETAL DYSPLASIAS
he lethal skeletal dysplasias are characterized by severe micromelia
and small thoracic circumference with pulmonary
hypoplasia. 51 he most important determinant of lethality is the
presence and degree of pulmonary hypoplasia. 11 In a prospective
series by Krakow et al., lethality was accurately predicted in 96.8%
of cases. 8 It is important to use multiple parameters to obtain
the most accurate prediction of lethality, typically related to the
pulmonary hypoplasia associated with a small chest. his
extremely high accuracy of the designation of a lethal skeletal
dysplasia is important for the management of the pregnancy,
delivery, and the newborn, if alive.
Features Suggestive of Pulmonary
Hypoplasia 52,53
• Thoracic circumference < ifth percentile, measured at
the level of the four-chamber view (axial view)
• Thoracic-to-abdominal circumference ratio < 0.6
• Short thoracic length (measured from the neck to the
diaphragm) as compared to nomograms
• Markedly narrowed anteroposterior diameter (sagittal
view)
• Concave or bell-shaped contour of the thorax (coronal
view)
• Femur length–to-abdominal circumference < 0.16
With permission from Krakow D, Lachman RS, Rimoin DL. Guidelines
for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med.
2009;11(2):127-133 52 ; Nelson DB, Dashe JS, McIntire DD, Twickler
DM. Fetal skeletal dysplasias: sonographic indices associated with
adverse outcomes. J Ultrasound Med. 2014;33(6):1085-1090. 53
A comparative study of eight methods for the prediction of
fetal lung hypoplasia determined that the lung volumes and the
thoracic circumference to abdominal circumference ratios
performed best. However, the majority of these studies were
performed in fetuses with congenital diaphragmatic hernia and
may not be generalizable to the skeletal dysplasia population. 6,54
Other studies showed that the femur-to-abdomen ratio (<0.16)
is more accurate in establishing lethality. 53
Is There a Lethal Skeletal Dysplasia?
CHARACTERISTIC FEATURES
Severe micromelia
Pulmonary hypoplasia
KEY DISTINGUISHING FEATURES
Abnormal mineralization
Fractures
Presence or absence of macrocranium
Thoracic length
In many fetal skeletal dysplasias, the skin and subcutaneous
layers continue to grow at a rate proportionately greater than
the long bones, resulting in relatively thickened skin folds, on
occasion mistaken for hydrops fetalis. Polyhydramnios is
common and may be related to a variable combination of
esophageal compression by the small chest, gastrointestinal
abnormalities, micrognathia, and/or hypotonia.
he more common lethal skeletal dysplasias occur in less
than 1 in 10,000 births and the rare types occur in less than 1
in 100,000 births. he three most common lethal skeletal dysplasias
are thanatophoric dysplasia, achondrogenesis, and OI
type II, overall accounting for 40% to 60% of all lethal skeletal
dysplasias. 5,8,55 here may be variations depending on location
and referral patterns; for example, in our tertiary referral care
center, the two most common groups were the OI and the
ibroblast growth factor receptor type 3 (FGFR3) chondrodysplasia
group, which includes thanatophoric dysplasia. 11