Sonographic diagnosis of fetal skeletal anomalies

Equinovarus foot twisted inwards
Equinus extended foot

Risk factors and clues to the diagnosis of skeletal anomalies

Family history

Although the majority of skeletal abnormalities are unexpected findings detected by ultrasound, some arise because of a relevant family history and others because of maternal drug use or maternal disease (Table 11.2). Whilst diagnosis can be more straightforward in families where there is an affected child or when one parent is affected with a dominantly-inherited condition, parents do need to be aware that some conditions, e.g., achondroplasia[3], may present relatively late in pregnancy, and others may be more variable, e.g., hypochondroplasia, and thus not necessarily amenable to sonographic diagnosis. For these reasons, molecular genetic diagnosis may be the best option for definitive diagnosis, but in most cases this will necessitate a detailed genetic work-up prior to pregnancy in order to identify relevant mutations. Molecular genetic diagnosis requires fetal tissue or DNA for analysis, which in the past has required an invasive test (chorionic villus sampling or amniocentesis). However, this is increasingly possible using noninvasive prenatal diagnosis (NIPD) and analysis of cell-free fetal DNA (cffDNA) in maternal plasma[4, 5]. In view of the rapid advances in molecular genetics, genetic advice should be sought before pregnancy in families of known high risk to be sure of the optimum method of diagnosis.

Table 11.2 Maternal factors associated with fetal skeletal abnormalities

Underlying etiology Fetal skeletal anomalies Other potential sonographic findings Other aids to diagnosis
Maternal drug ingestion
Warfarin Rhizomelic shortening of limbs. Stippled epiphyses, disorganized spine, mid-face hypoplasia, depressed nasal bridge and small nose Renal, cardiac and CNS anomalies Maternal medication history
Sodium valproate Forearm reduction deformity, polydactyly, oligodactyly, talipes Cardiac and CNS anomalies Maternal medical and medication history
Phenytoin Stippled epiphyses Micrognathia, cleft lip, cardiac anomalies Maternal medication history
Methotrexate Mesomelic shortening of long bones, hypomineralised skull, syndactyly, oligodactyly, talipes, micrognathia CNS anomalies including neural tube defects, Maternal medication history
Vitamin A Hypoplasia or aplasia of arm bones CNS and cardiac anomalies, spina bifida, cleft lip and palate, diaphragmatic hernia, exomphalos Maternal history
Alcohol Short long bones, forearm reduction deformity, pre-axial polydactyly of hands, oligodactyly, stippled epiphyses IUFGR, cardiac anomalies Maternal history
Cocaine Reduction deformities of arms +/− legs, ectrodactyly, hemivertebrae, absent ribs CNS, cardiac, renal anomalies, anterior abdominal wall defects, bowel atresias Maternal history. Hair root analysis for drug metabolites
Maternal disease
Insulin dependent diabetes Femoral hypoplasia often asymmetrical Short spine/caudal regression Glucose tolerance test
Myasthenia gravis Multiple joint contractures Decreased fetal movements Maternal anticholinesterase antibodies
Myotonic dystrophy Talipes Decreased fetal movements, polyhydramnios Maternal examination for signs of myotonia, facial appearance, family history, genetic referral
Systemic lupus erythematosus Short limbs, stippled epiphyses, depressed nasal bridge Autoantibody screen, maternal obstetric and medical history
Maternal hypothyroidism Short limbs, stippled epiphyses, depressed nasal bridge, stippling of spine, hands and feet Maternal obstetric and medical history, thyroid screen

CNS, central nervous system; IUFGR, intrauterine fetal growth restriction.

Maternal drug ingestion or disease

There are a number of drugs that may be implicated in the etiology of fetal skeletal anomalies (Table 11.2). Maternal conditions, such as insulin-dependent diabetes, myasthenia gravis and myotonic dystrophy, can cause a variety of skeletal problems (Table 11.2), with other conditions, such as systemic lupus erythematosis and hypothyroidism also causing skeletal changes, but less commonly. In maternal myasthenia gravis, even when the mother is asymptomatic, transmission of acetycholine receptor antibodies to the fetus can result in generalized arthrogryposis and neonatal or infant death. In mothers with symptomatic myotonic dystrophy (an autosomal dominant condition), there is an up to 50% chance of the baby having congenital myotonic dystrophy (Table 11.2), which carries a high neonatal mortality (around 20%), with most survivors having significant developmental delay and reduced life expectancy.

Fetal limb development and the timing of diagnosis

An understanding of the timing of the development of the fetal skeleton is essential for accurate sonographic diagnosis, particularly as there is an increasing tendency towards detailed anomaly scanning in early pregnancy. In the human, the upper limbs develop a few days in advance of the lower limbs, with the arm buds appearing at about 5 postmenstrual weeks. The clavicle begins to ossify at around 8 weeks gestation, followed by the mandible, vertebral bodies and neural arches around 9 weeks, the frontal bones at 1011 weeks and the long bones from 8 weeks (Figure 11.1)[6]. Of note, ossification of the cervical and sacral spine is not complete until around 20 weeks gestation. Most skeletal structures can be identified by 12 weeks gestation, but transvaginal scanning is recommended for accurate diagnosis at this gestation. In addition to sonographic expertise, accurate identification of skeletal anomalies requires aids such as charts of normal skeletal size, including length of long bones, clavicles, mandible, scapular, chest size, orbital diameters, renal size, etc.[710]. Given knowledge of skeletal development, sonographic expertise and necessary aids, and with the technologic advances in ultrasound platforms, it is clear that scanning in the first and early second trimesters can be ideal for the detection of many serious skeletal dysplasias (Tables 11.3 and 11.4;[11]) as well as localized limb reduction defects (Table 11.5;[12]).

Figure 11.1

Chart demonstrating gestation at which ossification of the fetal skeleton commences as indicated from radiologic studies of fetuses after delivery (adapted from Calder and Offiah[6]).

Table 11.3 A structured approach to the sonographic examination of a fetus presenting with short long bones and suspected to have a skeletal dysplasia

Examination Outcome Common diagnoses Other investigationsa
Measure all long bones All short IUFGR Maternal and fetal Dopplers. Review other biometry for small HC/AC. Serial scanning for growth velocity. Review maternal serum screening results for high hCG and MSAFP or low PAPP-A. Obstetric history for IUFGR, SB, PET, etc. Maternal medical history for autoimmune disease. Check for reduced AFI.
Constitutional short stature F/H, examine parents, normal long bone growth velocity, normal Dopplers.
Aneuploidy Detailed anomaly scan for markers of aneuploidy. Consider karyotyping.
Skeletal dysplasia See below
Assess the gestation at onset of shorteningb First trimester Thanatophoric, OI IIA/C/B, achondrogenesis types 1 and 2, most SRPSs, diastrophic dysplasia, SEDC, hypophosphatasia, Ellisvan Creveld, Boomerang dysplasia
Second trimester OI IIB/III/IV, Jeunes asphyxiating thoracic dystrophy, most chondrodysplasia punctatas
Third trimester Achondroplasia Exclude IUFGR, maternal blood for NIPD for FGFR3 mutations.
Compare measurements of proximal and distal long bones to classify type of shortening Rhizomelic shortening most evident in proximal long bones (humeri and femora) Diastrophic dysplasia, SEDC, Jeunes asphyxiating thoracic dystrophy
Mesomelic shortening of the mid-section of a limb (radius/ulna, tibia/fibula) Ellisvan Creveld, Achondroplasia, oral-facial-digital IV
Micromelic all long bones are very short Achondrogenesis type 1 and 2, Boomerang dysplasia
Evaluate the structure of bones Fractured/bowed OI type IIA/B/C/III/IV. Hypophosphatasia, campomelic dysplasia (legs only) Parental alkaline phosphatase levels, urinary phosphoethanolamine levels.
Hypomineralized OI type IIA/B/C/III Hypophosphatasia
Metaphyseal flaring Kniest syndrome
Absent bones Roberts syndrome Chromosome analysis for centromeric puffing.
Stippled epiphyses Rhizomelic chondrodyplasia punctata, Conradi Hunermann,
X-linked recessive chondrodyplasia punctate, warfarin embryopathy,
maternal SLE/auto-immune disease
Maternal drug history, mutations in ARSE gene, metabolic investigations very long chain fatty acids and sterol profile, maternal history of autoimmune disease.
Examine the extremities Polydactyly Jeunes asphyxiating thoracic dystrophy, Ellisvan Creveld syndrome, SRPSs Family history, check for consanguinity.
Syndactyly Apert syndrome NIPD for FGFR2 mutations.
Polysyndactyly SRPSs, oral-facial-digital IV
Oligodactyly De Lange, Roberts syndrome
Radial club hand VATER/VACTERL
Short fingers/trident hand Achondroplasia,
acromesomelic dysplasia,
thanatophoric dysplasia
Screen for mutations in FGFR3 gene.
Talipes Diastrophic dysplasia, campomelic dysplasia, Kniest, oral-facial-digital IV
Hitchhiker thumbs/toes Diastrophic dysplasia
Examine the skull size and shape Severe hypomineralisation OI IIA/C, achondrogenesis type 1, hypophosphatasia (severe neonatal type), Boomerang dysplasia
Mild hypomineralisation OI IIB (OI III), cleido-cranial dysostosis Examine the parents for cleido-cranial dysostosis.
Cloverleaf skull or craniosynostosis Thanatophoric dysplasia II, occasionally in SRPSs, Apert, craniosynostosis syndromes Maternal blood for NIPD to screen cfDNA for mutations in the FGFR3 and 2 genes.
Relative macrocephaly Thanatophoric dysplasia, achondroplasia, achondrogenesis type 1 Maternal blood for NIPD to screen cfDNA for mutations in the FGFR3.
Progressive microcephaly Rhizomelic chondrodysplasia punctate
Examine the clavicles and scapulae Short/absent clavicles Cleido-cranial dysostosis Examine parents.
Small scapula Campomelic dysplasia NIPT for fetal sex if genitalia are ambiguous or female.
Examine the face profile and coronal views Frontal bossing Achondroplasia, thanatophoric dysplasia, acromesomelic dysplasia Maternal blood for NIPD to screen cfDNA for mutations in the FGFR3 gene.
Micrognathia SEDC, Stickler syndrome, campomelic dysplasia, diastrophic dysplasia, Kniest syndrome Examine parents.
Consider NIPD for fetal sex if genitalia are ambiguous or female.
Cleft lip SRPSs Majewski syndrome, VermaNaumoff and BeemerLanger, Ellisvan Creveld, Roberts syndrome, oral-facial-digital IV
Absent/flat nasal bridge Rhizomelic chondrodysplasia punctata, Binder phenotype, Warfarin embryopathy Drug history, mutations in arylsulfatase E gene, metabolic investigations very long chain fatty acids and sterol profile, maternal history of autoimmune disease.
Mid-face hypoplasia Rhizomelic chondrodysplasia punctata, Binder phenotype, Kniest
Small nose Rhizomelic chondrodysplasia punctata, Binder phenotype, Kniest
Cataracts Rhizomelic chondrodysplasia punctate
Examine the thorax assess the size by measuring circumference by comparing with the abdomen in the axial plane or assessing lung:heart ratio. Examine the parasagittal view for the champagne-cork appearance Short SEDC, Stickler, Kniest Examine the parents.
Very small and narrow with champagne cork appearance Thanatophoric dysplasia,
SRPSs, dystrophy
achondrogenesis, OI IIA/C
Long and narrow Jeunes asphyxiating thoracic dystrophy. Occasionally achondroplasia and Ellisvan Creveld
Examine the ribs in the axial plane for length and sagittal/coronal plane for beading/fractures/missing ribs Short straight ribs Thanatophoric dysplasia, SRPSs, Jeunes asphyxiating thoracic dystrophy, achondrogenesis type 2, Ellisvan Creveld , achondrogenesis type 1
Fractures/beaded ribs OI IIA/C/B
Absent/disorganized ribs JarcotLevin, spondylocostal dysplasia, campomelic dysplasia (occasionally only 11 ribs).
Examine the spine for mineralization, disorganization, hemivertebrae Hypomineralized vertebral bodies Achondrogenesis type I
Hemivertebrae VATER/VACTERL
Spondylocostal dysplasia
Disorganization (may be confused with extra calcification) JarcotLevin, spondylocostal dysplasia, some chondrodysplasia punctatas, dyssegmental dysplasia,
Examine the skin for edema Increased nuchal translucency Thanatophoric, OI, SRPSs, SEDC and several others
Hydrops SRPSs, achondrogenesis type 1, Boomerang dysplasia
Examine the fetal viscera CNS anomaly SRPSs (Majewski, BeemerLanger), thanatophoric dysplasia type II, occasionally achondroplasia
Cardiac anomaly Campomelic dysplasia, Ellis van Creveld, SRPSs, VATER/VACTERL
Renal tract anomaly Jeunes asphyxiating thoracic dystrophy, SRPSs
Anterior abdominal wall defect SRPS (BeemerLanger)
Genital anomalies Campomelic dysplasia, SRPSs NIPD for fetal sex determination
Amniotic fluid volume Polyhydramnios Achondroplasia, thanatophoric dysplasia, paternal uniparental disomy 14, VATER/VACTERL
Oligohydramnios SRPSs with renal anomalies.

a Investigations recommended if other features are compatible with a diagnosis.

b There is variability for some dysplasias and the timings given here reflect the authors personal experience. In addition, where there is a family history scanning may be targeted at certain features that may otherwise be overlooked on a routine scan facilitating earlier diagnosis.

AC: abdominal circumference; AFI: amniotic fluid index; cfDNA: cell-free DNA; CNS: central nervous system; FGFR3: fibroblast growth factor 3; HC: head circumference; hCG: human chorionic gonadotropin; IUFGR: intrauterine fetal growth restriction; MSAFP: maternal serum alpha-fetoprotein; SRPS: short-ribbed polydactyly syndrome; NIPT: noninvasive prenatal testing; OI: osteogenesis imperfecta; PAPP-A: pregnancy-associated plasma protein A: PET: pre-eclamptic toxemia; SB: stillbirth; SEDC: spondylo-epiphyseal dysplasia congenica; SLE: systemic lupus erythema; VATER/VACTERL: vertebral anal atresia tracheoesophageal fistula radial anomaly/vertebral anal atresia cardiac trachea-esophageal fistula radial limb anomaly.

Table 11.4 Early sonographic features of skeletal dysplasias potentially identifiable by ultrasound by 14 weeks gestation[12]

Condition NT FL HC Thorax Skull Other features Inheritance Gene Lethal (Y/N) Aids to diagnosis
Achondrogenesis I + <5th N Small N
Poor ossification
Hydrops, hypomineralized vertebral bodies AR 1A TRIP11
Achondrogenesis II + <5th Narrow, short ribs No ossification No/minimal ossification of vertebral bodies, poorly ossified long bones, generalized oedema AD COL2A1 Y
Ellisvan Creveld +/− <5th N Small N Cardiac anomaly, polydactyly, posterior fossa cyst AR EVC1, EVC2 N
Osteogenesis imperfecta IIA/C + <5th N Small Hypomineralized Short ribs, crumpled long bones, acute angling of femora AD (AR) COL1A1/ COL1A2 and others Y
Osteogenesis imperfecta IIB/III N/<5th N N/
slightly small
May have slightly poor mineralization Bowed long bones AD (AR) COL1A1/ COL1A2
and others
Thanatophoric dysplasia + 5th/<5th N/
Narrow, short ribs N/abnormal shape (cloverleaf) Frontal bossing,
bowed femora, short fingers
AD FGFR3 Y NIPD to screen cfDNA for FGFR3 mutations
Campomelic dysplasia + <5th
N Small N Club feet, tibial spikes, arms normal length and appearance AD SOX9 Y/N
Diastrophic dysplasia + <5th N N N Hitchhiker thumb, clubfoot, all long bones <5th AR SLC26A2 N
Congenital hypophosphatasia +/− <5th / 10th N N/
narrow, short ribs
Hypomineralized Poorly ossified ribs, vertebrae and long bones, polyhydramnios, short long bones, talipes AR TNSALP Y Parental alkaline phosphatase levels
Greenberg skeletal dysplasia + <<3rd N Narrow N Hydrops, hepatomegaly, severe generalised micromelia AR LBR Y
Spondylo-epiphyseal dysplasia congenita + N 5th N Short N Hypomineralized vertebral bodies AD COL2A1 N
Boomerang dysplasia + <<5th Short, small Hypomineralized Some long bones not visible X-linked
Jeunes asphyxiating thoracic dystrophy +/− <5th N Narrow, short ribs N Polydactyly AR DTNCH2H1
SRPS I (SaldinoNoonan) + <<3rd N Small N Generalized skin edema, severe micromelia, polydactyly AR Y
SRPS II (Majewski) + 5th/<<3rd N Small, short ribs N/cloverleaf Exomphalos, bladder outflow obstruction, polydactyly, generalized edema AR DYNCH2H1, NEK1 Y
SRPS III (Verma-Naumoff syndrome) + <10th Small N Postaxial polydactyly DTNCH2H1 Y
Blomstrand dysplasia + <5th Flared metaphyses, generalized rhizo-
meso-acromelic limb shortening
Roberts syndrome + <5th N Oligodactyly, short long bones, talipes, facial cleft AR ESCO2 Y/N Fetal chromosome puffing
Cleido-cranial dysplasia + N/slightly short Hypomineralized Poor ossification of the vertebral spine, hypoplastic clavicle AD RUNX2 N

Adapted from reference 12. AD, autosomal dominant; AR, autosomal recessive FL, femur length; HC, head circumference; NT, nuchal translucency; SRPS, short-ribbed polydactyly syndrome.

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Apr 14, 2017 | Posted by in PEDIATRICS | Comments Off on Sonographic diagnosis of fetal skeletal anomalies
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