Key Points
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Diagnosis of skeletal anomalies is challenging and requires time and a team approach, including clinical geneticists, paediatricians and pathologists.
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This chapter deals with the prenatal diagnosis of skeletal anomalies. It gives aids to diagnosis and categorises conditions by sonographic findings to help sonographers narrow the differential diagnoses.
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Increasingly, with advances in genomic medicine, the definitive diagnosis can be achieved prenatally after targeted molecular genetic or metabolic investigations, sometimes by safe approaches using analysis of cell-free DNA in maternal blood.
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In the absence of a definitive diagnosis prenatally, expert postmortem examination, including radiology or genome sequencing, should be offered for a diagnosis, which is essential to define recurrence risks (which can vary from 1% to 50%) and appropriate prenatal diagnosis in subsequent pregnancies.
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Molecular genetic diagnosis facilitates early prenatal diagnosis in subsequent pregnancies, and storage of DNA should be encouraged, particularly in cases with an unknown diagnosis as the genetic aetiology for these conditions is increasingly being defined.
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This is a rapidly moving field, and discussion with geneticists is helpful to ensure the most up-to-date information is available.
Introduction
Congenital skeletal anomalies are not uncommon, occurring with an incidence of around 1 in 500. Many are amenable to prenatal detection using ultrasound. The underlying aetiology is varied and includes:
Aneuploidy
Genetic syndromes
Skeletal dysplasias
Teratogens
Isolated anomalies secondary to disruption
The sonographic detection of a fetus with a skeletal anomaly can present a challenging diagnostic dilemma. Management options can be very varied, and diagnosis may require biochemical, genetic or haematologic investigation. Increasingly more sophisticated imaging, such as magnetic resonance imaging (MRI) or computed tomography (CT), may elucidate features more easily interpreted by postnatal radiologists. Clinical genetic input is invariably useful, not only because the family history or parental examination may yield valuable clues to the diagnosis but also because this is a field that is evolving rapidly. The underlying genetic aetiology of skeletal dysplasias are increasingly known, and new, safer, approaches to prenatal diagnosis based on analysis of cell-free DNA (cfDNA) are being used.
This chapter discusses the normal embryology and sonographic appearances of fetal limb development and go on to suggest a systematic approach to the diagnosis of fetal skeletal anomalies, as well as describing some of the more common conditions in greater detail. Generalised skeletal dysplasias are discussed as well as those groups of conditions associated with more localised limb anomalies, which may or may not be part of a wider genetic syndrome. Accurate sonographic identification of skeletal abnormalities becomes increasingly important as more genes for skeletal conditions are identified, raising the potential for accurate prenatal diagnosis using molecular methods.
Terminology
Fetal ultrasound diagnosis relies on the identification and accurate description of sonographic findings. Skeletal anomalies are associated with a range of genetic syndromes and dysplasias, and discussion with other specialists (in particular clinical geneticists, radiologists and orthopaedic surgeons) is necessary to try to define both the diagnosis and prognosis to inform accurate parental counselling. To be able to do this efficiently, a good understanding of terminology is required. Normal bone nomenclature is illustrated in Fig. 34.1 . The terminology used in describing abnormalities of the limbs is given in Table 34.1 .
| Acheiria | Absent hand(s) | ||
| Acheiropodia | Absent hand(s) and feet | ||
| Acromelia | Shortening of the distal segments of limbs (i.e., hands and feet) | ||
| Adactyly | Complete absence of fingers, toes or both | ||
| Amelia | Complete absence of one or more limbs from the shoulder or pelvic girdle | ||
| Apodia | Absent foot (feet) | ||
| Arthrogryposis | Congenital joint contractures | ||
| Brachydactyly | Short digits | ||
| Camptomelia | Bent limb | ||
| Camptodactyly | Bent digit(s) | ||
| Clinodactyly | Incurved fifth finger | ||
| Ectrodactyly | Split (cleft) hand(s) or feet, missing central ray(s), lobster claw deformity | ||
| Hemimelia | Congenital longitudinal absence or deficiency of a forearm or lower leg bone | ||
| Kyphosis | Dorsal convex curvature of the spine | ||
| Kyphoscoliosis | Combination of lateral and anteroposterior curvature of the spine | ||
| Meromelia | Partial absence of a limb | Transverse | Defect extending across the whole width of the limb |
| Longitudinal | Defects affecting one bone along an axis | ||
| Terminal | No bony part distal to the defect | ||
| Intercalary | With recognisable parts distal to the defect | ||
| Mesomelia | Shortening of the middle segment of a limb (i.e., radius/ulna and tibia/fibula) | ||
| Micromelia | Shortening of all long bones | ||
| Oligodactyly | Absent or partially absent digit(s) | ||
| Phocomelia | Relatively normal hands or feet are attached to the trunk either directly or by extremely shortened long bones | ||
| Platyspondyly | Flattening of the vertebral bodies | ||
| Polydactyly | Extra fingers or toes | Preaxial | Extra digit on the radial or tibial side |
| Postaxial | Extra digit on the ulna of fibular side | ||
| Rhizomelia | Shortening of the proximal long bones (i.e., femur and humerus) | ||
| Syndactyly | Fused digital rays | Skin | Fused skin only |
| Osseous | Bony fusion | ||
| Scoliosis | Lateral curvature of the spine | ||
| Talipes | Club-foot | Equinovalgus | Foot twisted outwards |
| Equinovarus | Foot twisted inwards | ||
| Equinus | Extended foot |
Embryology and Sonographic Appearance of the Normal Fetal Skeleton
In humans, the upper limbs develop a few days in advance of the lower limbs, with the arm buds appearing at about 5.5 postmenstrual weeks. The fetal skeleton then forms in two ways, membranous ossification (clavicle and mandible) and intracartilaginous (endochondral) when ossification occurs by calcium deposition in preexisting cartilage matrix. Fetal ossification begins in the clavicle at around 8 weeks’ gestation followed by the mandible, vertebral bodies and neural arches at around 9 weeks; the frontal bones at 10 to 11 weeks; and the long bones at around 11 weeks. Most skeletal structures can be identified sonographically by 14 to 15 weeks. The appearance of the ossification in the fetal skeleton has been studied both radiographically and sonographically using transabdominal ultrasound. However, probably the most useful indication of which structures should be identified when scanning in early pregnancy comes from a recent radiologic study of human fetuses ( Fig. 34.2 ). Identification of anomalies of skeletal development requires detailed scanning and aids such as charts of normal skeletal size, including length of long bones, clavicles, mandible, scapulae, chest size, orbital diameters, renal size and so on.
Classification of Skeletal Dysplasias
The genetic and pathological aetiology of skeletal anomalies is wide, and there have been several classifications used. These have evolved as understanding of the genetics and pathophysiology of these rare but complex disorders becomes clearer. Classifications can be based on clinical or radiological features (or both), molecular genetic aetiology or the biological structure and function of genes and proteins involved (e.g., defects in structural proteins, metabolic pathways, transcription factors etc.) or a hybrid of both. A classification based on sonographic findings is the most useful classification for the prenatal diagnostician ( Table 34.2 ), but there can be considerable overlap in conditions, so a table listing the common diagnoses with gene location, when known; inheritance; and main sonographic findings is also given ( Table 34.3 ).
| Sonographic finding | Condition | Other investigations to be considered |
|---|---|---|
| Skull | ||
| Hypomineralised | Osteogenesis imperfecta types IIA and IIC Achondrogenesis type I Hypophosphatasia (severe neonatal form) | Parental fracture history for possible somatic mosaicism a a Parental ALP and urinary phosphoethanolamine a |
| Mild hypomineralisation | Achondrogenesis type 2 Cleidocranial dysostosis Osteogenesis imperfecta IIB | a Parental history a Parental history as above |
| Cloverleaf | Thanatophoric dysplasia type II Occasionally in SRPSs Antley-Bixler syndrome Craniosynostosis syndromes (Pfeiffer, Crouzon, Saethre-Chotzen syndromes) | NIPD a a a a |
| Spine | ||
|---|---|---|
| Hypomineralised | Achondrogenesis type I | ∗ |
| Disorganised | Jarcho-Levin syndrome Spondylocostal dysplasia Dyssegmental dysplasia Some chondrodysplasia punctatas VATER/VACTERL | Consider metabolic screening a |
| Face | ||
| Frontal bossing | Thanatophoric dysplasia Achondroplasia Acromesomelic dysplasia | NIPD |
| Depressed nasal bridge | Chondrodysplasia punctatas Warfarin embryopathy | Drug history, karyotype, ARSE deletion screen (CDPX1) a Metabolic investigations: very-long-chain fatty acids and sterol profile, CVS for peroxisomal enzyme studies, maternal history of autoimmune disease |
| Micrognathia | SEDC Stickler syndrome Campomelic dysplasia | Karyotype a a a |
| Cleft lip | Majewski syndrome Oral facial defect IV | a a |
| Legs | ||
|---|---|---|
| Isolated straight, short long bones | IUGR Constitutional short stature | Fetal and maternal Doppler, maternal Down syndrome screening biomarkers, obstetric history |
| Femoral bowing | Campomelic dysplasia Osteogenesis imperfecta Hypophosphatasia | As above a a a |
| Talipes | Campomelic dysplasia Diastrophic dysplasia | NIPD for sex determination a a |
| Stippled epiphyses | Rhizomelic chondrodysplasia punctata Conradi Hunermann syndrome X-linked recessive chondrodysplasia punctata Warfarin embryopathy Maternal SLE | Drug history, metabolic investigations; very-long-chain fatty acids and sterol profile, CVS peroxisomal enzyme studies, a maternal history of autoimmune disease |
| Thorax | ||
|---|---|---|
| Narrow with short ribs | SRPSS Jeune asphyxiating thoracic dystrophy Thanatophoric dysplasia Osteogenesis imperfecta types IIA, C and B Campomelic dysplasia Achondrogenesis Hypochondrogenesis Paternal UPD14 | a a NIPD a a a a a a |
| Beaded ribs | Osteogenesis imperfecta type IIA and C | a |
| Polyhydramnios | Achondroplasia Thanatophoric dysplasia Paternal UPD14 | NIPD a NIPD a a |
| Diagnosis | Gene or location | Genetics | Gestational age at presentation (wk) | Limbs | Thorax | Spine | Skull | Other Features | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Short | Bowed | Fingers | Joints | Ribs | ||||||||
| Achondrogenesis IA/IB | TRIP11 (1A); SLC26A2 (DTDST) (1B) | AR | 12 | +++ | Narrow | Short, +/- beaded | Hypo | Hypo | Oedema | |||
| Achondrogenesis II | COL2A1 | AD | 12 | ++ | Narrow | Short | ||||||
| Achondroplasia | FGFR3 | AD | >24 | + | +/- mild | Short | +/- small | Frontal bossing | ||||
| Acromesomelic dysplasia | NPR2, GDF5, BMPR1B | AR | Around 22 | + | Short | +/- small | Frontal bossing | |||||
| Beemer-Langer | Unknown | AR | Around 20 | + | Poly | Small | Short | Cloverleaf | ||||
| Campomelic dysplasia | SOX9 | AD | 16–20, var | Legs | Legs | Talipes | +/- small | Micrognathia, cardiac defects, sex reversal in males | ||||
| Conradi Hunermann CDP (CDPX2) | EBP | XLD | Var | + Stippled | Stippled | |||||||
| Diastrophic dysplasia | SLC26A2 (DTDST) | AR | >16 | + | Hitchhiker thumbs | Talipes | Micrognathia | |||||
| Ellis-van Creveld syndrome | EVC, LBN (EVC2 | AR | From 16 | + | Poly | Narrow | Short | Cardiac anomaly | ||||
| Hypophosphatasia (severe neonatal form) | TNSALP | AR | >12 | ++ | ++ | Hypo | ||||||
| Jeune asphyxiating thoracic dystrophy | IFT80, DYNCH2H1, TTC21B, WDR19 and > 6 others | AR | From 16, variable | + | +/- poly | Narrow | Short | CNS anomaly | ||||
| Kniest syndrome | COL2A1 | AD | Variable | + | Mild | Short | Micrognathia, depressed nasal bridge | |||||
| Majewski syndrome (SRPS2A; SRTD6) | NEK1 | AR | >12 | ++ | Ovoid tibia | Poly | Narrow | Short ++ | Renal, cardiac, CNS, genital | |||
| Osteogenesis imperfecta types IIA/C and IIC | COL1A1 COL1A2 | AD, gm | >12 | +++ | +++ | Narrow | Short, beaded | Hypo | ||||
| Osteogenesis imperfecta type IIB | COL1A1 COL1A2 | AD, gm | >16 | ++ | + | (Narrow) | (Beaded) | |||||
| Osteogenesis imperfecta type III | COL1A1 COL1A2 | AD, gm | 20 | + | Legs | |||||||
| Osteogenesis imperfecta type IV | COL1A1 COL1A2 | AD, gm | >20 | Mild, femora | ||||||||
| Rhizomelic CDP (RCDP1,2,3,5) NB Overlapping heterogeneous peroxisomal disorders, Zellweger syndrome | PEX7, GNPAT, AGPS, PEX5 | AR | 20 | Rhizomelic stippled | Stippled | Nasal hypoplasia, cataracts | ||||||
| Saldino-Noonan syndrome (SRPS2B; SRTD3; ATD3) | DYNC2H1 | AR | >12 | ++ | Poly | Narrow | Short ++ | Renal, cardiac, genital | ||||
| SEDC | COL2A1 | AD | >12 | ++ | Short | Micrognathia | ||||||
| Thanatophoric dysplasia I | FGFR3 | AD | <16 | Severe micromelia | (Mild) | Short trident | Small ++ | Short ++ | Normal | Frontal bossing | ||
| Thanatophoric dysplasia II | FGFR3 | AD | <16 | Severe micromelia | (Mild) | Short, trident | Small++ | Short ++ | Cloverleaf | Frontal bossing | ||
| X-linked recessive CDP (CDPX1) | ARSE | XLR | Variable | + stippled | Short | Stippled | Stippled larynx and trachea |
Clues to the Diagnosis of Skeletal Anomalies
Risk factors for skeletal anomalies include:
Family history
Drugs in early pregnancy
Maternal disease
Abnormal findings on routine ultrasound
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).
| Drug or substance | Skeletal anomalies | Other sonographic findings |
|---|---|---|
| Warfarin | Rhizomelic shortening of limbs, stippled epiphyses, kyphoscoliosis | Flat face; depressed nasal bridge; renal, cardiac and CNS anomalies |
| Sodium valproate | Reduction deformity of arms, polydactyly, oligodactyly, talipes | Cardiac and CNS anomalies, spina bifida, orofacial clefting |
| Methotrexate | Mesomelic shortening of long bones, hypomineralised skull, syndactyly, oligodactyly, talipes | CNS anomalies, including neural tube defects, micrognathia |
| Vitamin A | Hypoplasia or aplasia of arm bones or digits | CNS and cardiac anomalies, spina bifida, cleft lip and palate, diaphragmatic hernia, exomphalos |
| Phenytoin | Stippled epiphyses | Micrognathia, cleft lip, cardiac anomalies |
| Alcohol | Short long bones, reduction deformity of arm bones, preaxial polydactyly of hands, oligodactyly, stippled epiphyses | IUGR, cardiac anomalies |
| Cocaine | Reduction deformities of arms +/- legs, ectrodactyly, hemivertebrae, absent ribs | CNS, cardiac, renal anomalies, anterior abdominal wall defects, bowel atresias |
Maternal Disease
The most common maternal conditions that can result in fetal musculoskeletal anomalies ( Table 34.5 ) include:
Diabetes
Myasthenia gravis
Myotonic dystrophy
| Sonographic findings | Maternal condition | Maternal diagnosis |
|---|---|---|
| Caudal regression Femoral hypoplasia | Diabetes | Glucose tolerance test |
| Multiple joint contractures (arthrogryposis) | Myasthenia gravis | Anti–acetylcholine receptor antibodies |
| Talipes and polyhydramnios | Myotonic dystrophy | Examine for signs of myotonia, facial appearance, genetic referral |
| Short limbs, stippled epiphyses, depressed nasal bridge | Systemic lupus erythaematosus | Autoimmune screen, history |
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