Diagnosis and Management of Fetal Skeletal Abnormalities

Family History

Clearly, diagnosis in families in which there has already been an affected child or when one parent is affected with a dominantly inherited condition can be more straightforward than interpretation of findings that arise de novo . For some dominantly inherited conditions, one parent may manifest mildly or subclinically because of somatic (alteration in the DNA that occurs after conception) mosaicism but be at high risk for a more severely affected offspring who has inherited the mutation constitutively (nonmosaic), examples including osteogenesis imperfecta (OI) and spondyloepiphyseal dysplasia congenita (SEDC).

Knowledge of the sonographic features and natural history of the condition can aid prenatal diagnosis, but parents do need to be aware that some conditions (e.g., achondroplasia) may present relatively late and not be amenable to sonographic diagnosis until well into the second trimester. Others are more variable (e.g., hypochondroplasia) and are not obvious until after birth or in early childhood. For these reasons, molecular diagnosis may be preferable in families in which the gene has been identified before pregnancy. In the past, this required an invasive test (chorionic villus sampling) with its small risk for iatrogenic miscarriage to obtain fetal genetic material for testing. However, technical advances have made noninvasive prenatal diagnosis (NIPD) based on analysis of cell-free fetal DNA in maternal blood possible for several skeletal dysplasias. If the precise mutation is known before pregnancy, then bespoke NIPD may be possible.

With rapid advances in molecular genetics, the underlying genetic aetiology for many of these conditions is known, and it is imperative that tissue is available from affected pregnancies if parents are subsequently to be given the opportunity of early testing. Many conditions are heterogeneous (meaning that the causative mutation(s) may reside in any one of a number of different genes) so that extensive genetic analysis before pregnancy may be required before prenatal molecular testing can be offered. Many families may wish to avoid the risks associated with invasive prenatal testing. The advent of noninvasive prenatal testing using free fetal DNA in the maternal plasma means that parents are increasingly able to get a diagnosis without risk as this technology progresses. Nonetheless, genetic workup before pregnancy will be required for this technology as well as for traditional invasive testing.

Drugs in Early Pregnancy

Although drugs are now extensively tested before release onto the market, there are still those used regularly that may result in skeletal malformations if taken in early pregnancy ( Table 34.4 ). Furthermore, there is good evidence that some recreational drugs, if used in early pregnancy, can cause skeletal anomalies, a postulated vascular effect being responsible for some drugs (e.g., cocaine).

Maternal Disease

The most common maternal conditions that can result in fetal musculoskeletal anomalies ( Table 34.5 ) include:

• Diabetes

• Myasthenia gravis

• Myotonic dystrophy

Other conditions such as systemic lupus erythaematosus (SLE) and hypothyroidism can also cause skeletal changes but less commonly. Poorly controlled, insulin-dependent diabetes is the most common maternal condition that can result in significant skeletal anomalies in fetuses, which include developmental field defects of the spine, vertebral segmentation defects, caudal regression syndrome and deficiencies of the limbs (particularly femoral hypoplasia, tibial hemimelia, preaxial hallucal polydactyly) as well as anomalies of other viscera, in particular the heart and urogenital tract.

In maternal myasthenia gravis, transmission of acetylcholine receptor antibodies to the fetus can result in generalised arthrogryposis and neonatal or infant death. In some instances, the antibodies are specific to the fetal subunit of the acetylcholine receptor, and the mother may be asymptomatic.

Myotonic dystrophy is an autosomal dominantly inherited condition which, when transmitted maternally to the fetus, can result in congenital myotonic dystrophy (CMD). Mothers with clinically detectable neuromuscular manifestations of myotonic dystrophy have between a 10% and 50% risk for having a baby with CMD. In pregnancy, characteristic sonographic findings include talipes, decreased fetal movements or breathing and polyhydramnios. Affected neonates are very floppy and often have respiratory problems requiring ventilatory support, and the mortality rate is high (20%). Most survivors have significant developmental delay and a reduced life expectancy. The finding of talipes and polyhydramnios in a euploid fetus should prompt examination of the mother for signs of myotonic dystrophy.

Maternal SLE can cause a variety of problems in fetuses, including limb shortening with stippled epiphyses; facial anomalies, in particular a depressed nasal bridge; and an abnormal appearance of the spine secondary to extra calcification. Other findings can include bradycardias, growth retardation and hydrops.

Abnormal Findings on Routine Ultrasound

The first clue that there may be a skeletal anomaly present is often the identification of a short femur at the time of a scan for another reason, either a routine fetal anomaly scan at around 20 weeks’ gestation or a scan later in pregnancy for other indications. Careful examination of the rest of the fetal anatomy can reveal further signs of a skeletal dysplasia ( Table 34.6 ). If limb shortening appears to be isolated, then intrauterine growth restriction (IUGR) must be considered as a possible aetiology. In these circumstances, review of maternal serum screening results for levels of pregnancy-associated plasma protein A (PAPP-A), β-human chorionic gonadotrophin (β-hCG) and maternal serum alphafetoprotein (MSAFP) and assessment of fetal and maternal Dopplers can be useful diagnostic aids. In a 4-year period at University College London Hospital of 130 fetuses referred with ‘abnormal’ femora (short, bowed, hypoplastic), 42 fetuses were thought to have short, straight femurs or limbs with no other sonographic abnormalities detected. Only 2 of these had a skeletal dysplasia. Many were normal and had either had an incorrect assignment of gestational age or familial short stature, but 31% had IUGR.

Skull

The skull should normally be rugby ball in shape and cast a good acoustic shadow, indicating normal mineralisation. Decreased mineralisation is indicated by an anechoic skull vault, which casts little or no acoustic shadow ( Fig. 34.3 ). Furthermore, the intracranial contents will be more clearly visualised than normal, and because the cerebral hemispheres appear relatively anechoic, the appearances are not infrequently mistaken for cerebral ventriculomegaly. Careful examination will reveal the characteristic and hyperechoic, normally located, choroid plexus (see Fig. 34.3 ). In conditions associated with hypomineralisation in later pregnancy, the skull shape can readily be deformed by pressure from the transducer. Variation in skull shape can be seen rarely in some craniosynostosis syndromes, and a cloverleaf skull is also seen in thanatophoric dysplasia type II.

Spine

The spine should be examined carefully in all three orthogonal planes. There may be absent or decreased mineralisation, but it must be remembered that ossification of the cervical and sacral vertebral bodies is a late event; the sacral vertebral bodies are not ossified until 27 weeks’ gestation. Vertebral segmentation anomalies (hemivertebrae, butterfly vertebrae, fused vertebrae) ( Fig. 34.4A and B ) can occur with or without associated rib anomalies. The appearance of general disorganisation may indicate ectopic calcification seen in some chondrodysplasia punctates (see Fig. 34.4B and C ) or bony developmental abnormalities as in Jarcho-Levin syndrome and other spondylocostal dysplasias, VACTERL association (vertebral anomalies, anorectal malformations, cardiovascular anomalies, tracheoesophageal fistula, oesophageal atresia, renal (kidney) or radial anomalies and limb defects) and maternal diabetes (see Fig. 34.4E ).

Face

Many skeletal dysplasias have associated facial anomalies. The face should be examined in the coronal view to exclude a cleft lip, which in some conditions, such as oral facial digital syndrome type IV or Ellis-van Creveld syndrome, can be very small and difficult to detect ( Fig. 34.5 ). An axial view of the palate should be visualised in order to detect significant degrees of cleft palate, which can be associated with several dysplasias. A sagittal view will reveal micrognathia, flattening of the facial profile, frontal bossing or a depressed nasal bridge. Measurement of the mandible and orbital diameters can be useful but may be more difficult to achieve in later pregnancy with increasing acoustic shadowing from surrounding bony structures.

Long bones

Length of long bones should be checked against appropriate charts of long bones length. The pattern of shortening is a useful diagnostic aid. There may be generalised shortening of all long bones (micromelia). It may be more marked in the proximal long bones (rhizomelia) or the forearms and lower legs (mesomelia). In some conditions, the changes may be confined to the legs (e.g., campomelic dysplasia) or arms (e.g., Holt Oram syndrome). Deformation of the bones is a very useful diagnostic feature. The position and degree of bowing or fracturing should be noted. Bones may appear short, thick and crumpled, indicating severe degrees of fracturing and undermodelling (see images of fetuses with OI in Fig. 34.9 ). Deformity; hypoplasia; or absence of tibia, fibula, radius or ulna may be present. The ends of the bones should be carefully examined to exclude epiphyseal stippling that might indicate a chondrodysplasia punctata. If stippling is identified, various metabolic and cytogenetic investigations can be done to define the underlying aetiology (see section on chondrodysplasia punctata and Fig. 34.20 for examples). Expanded metaphyses may be seen in Kniest syndrome.

Thorax

Many lethal dysplasias are associated with thoracic abnormalities. Nomograms of thoracic circumference are available, but a small chest can often be identified by observation alone. In normal circumstances, the thorax and abdomen should be approximately the same size viewed in the axial plane, and sonographic comparison can help indicate a small chest as, for example, in OI and thanatophoric dysplasia (see Figs. 34.10 and 34.12 in these sections for examples). The heart should normally occupy one third of the chest. If the ribs are short, the heart will appear to occupy a greater proportion of the chest when viewed in the axial plane and, when there is extreme shortening of the ribs, as, for example, in thanatophoric dysplasia, the heart may appear to lie outside the thoracic cavity (see Fig. 34.12 ). In the sagittal section, the thorax will be narrow and the abdomen protuberant, a configuration that has given rise to the expression ‘champagne-cork appearance’. The chest can also be small secondary to a short spine, as in some of the spondylodysplasias. In these situations, the chest may appear small in a sagittal plane but, when viewed in the axial plane, the ribs appear of normal length and the heart occupies the appropriate proportion of the thoracic cavity (see Fig. 34.14 ). The ribs themselves should be examined carefully as they may be short, thick, thin, beaded or irregular in organisation or number. Short ribs (extending less than halfway around the chest in transverse section) can be viewed in the axial plane (see Figs. 34.7, 34.10 and 34.12 for examples), and they should be examined in a longitudinal plane to exclude beading, which is indicative of fracturing (see Figs. 34.9 and 34.10 ). Disorganisation of the ribs (and spine) may be features of conditions such as Jarcho-Levin syndrome (see Fig. 34.4E ).