Skeletal Radiology in Children: Non-Traumatic and Non-Malignant

Nomenclature

The naming of constitutional disorders of bone can be confusing. Constitutional bone disorders include osteochondrodysplasias and dysostoses. Osteochondrodysplasias consist of dysplasias (abnormalities of bone and/or cartilage growth) and osteodystrophies (abnormalities of bone and/or cartilage texture). Osteochondrodysplasias are due to intrinsic abnormalities in bone and cartilage, and because of gene expression will continue to evolve throughout the life span of the individual.

Dysostoses occur as a result of a more discrete ‘hit’ during skeletal development—typically during blastogenesis in the first 6 weeks of intrauterine life. The phenotype is fixed, therefore, although multiple bones may be involved and the abnormality may grow with the child, the previously normal bones will remain so. Whilst most dysostoses are genetically determined, some are caused by environmental effects—such as amniotic bands or toxic effects of warfarin; in these cases the abnormality may be termed a ‘disruption’.

Some of the confusion between dysplasias and dysostoses/disruptions arises as a result of unfortunate historical mislabelling of conditions. For instance, the constellation of bony changes often called ‘dysostosis multiplex’ seen in the mucopolysaccharidoses, which are technically dysplasias. The 2015 International Nosology and Classification of Genetic Skeletal Disorders includes 436 different conditions subdivided into 42 groups defined by molecular, biochemical and/or radiographic findings. The classification includes 364 different genes—an increase on the 226 identified in the 2011 classification, with an ever-expanding number of genes continuing to be identified. Selected conditions are summarised in Table 73.1 ( Figs 73.1 to 73.31 ).

While the international classification lists only those conditions with a proven genetic basis, there are currently over 2000 malformation syndromes, many of which are associated with skeletal abnormalities and many constitutional disorders of bone for which the genetic basis is unknown. In this chapter, only an approach to diagnosis can be given and only the more common conditions are used as illustrative examples.

Prevalence

Although individually rare, collectively, malformation syndromes and constitutional disorders of bone form a large group. As a rough estimate, approximately 1% of live births have clinically apparent skeletal abnormalities. This figure does not take into account the large numbers of spontaneous abortions or elective terminations, many of which have significant skeletal abnormalities. Nor does it include those dysplasias presenting only in childhood, or those relatively common conditions that may never present for diagnosis because they are mild—for example, hypochondroplasia and dyschondrosteosis—both of which merge with normality in individual cases. In addition, there is wide variation in the incidence of dysplasias between populations—for instance, the rate of achondroplasia is as high as 1 in 6400 live births in Denmark, but only 1 in 10,000 in Latin America. At orthopaedic skeletal dysplasia clinics in England and Scotland, approximately 10,000 patients are seen, 6000 of whom will require repeated hospitalisation for surgical procedures and some will require more prolonged admissions.

Diagnosis

Arriving at an accurate diagnosis requires a multidisciplinary approach, with combined clinical, paediatric, genetic, biochemical, radiological and pathological (molecular, cellular and histopathological) input ( Table 73.2 ). A diagnosis is not always made at the time of first presentation and can sometimes take several years to definitively establish.

There are two broad approaches to the diagnosis of osteochondrodysplasias and dysostoses: primary clinico-radiological and primary genetic.

Traditionally, diagnosis was made primarily on the basis of clinical features, such as cleft palate and myopia, combined with careful evaluation of radiographic features. The radiographic evaluation involves multiple elements: identifying the site and nature of abnormalities—for example, whether a dysplasia is affecting epiphyses (epi-), metaphyses (meta-) or the spine (spondylo-); identifying the pattern and distribution of changes (e.g. distal (acro-) ( Fig. 73.32 ) or proximal (rhizo-) shortening); and looking for patterns of bone changes that suggest involvement of a particular gene (e.g. narrow interpedicular distances in FGFR3 conditions). Rapid advances are being made in the field of gene mapping, with many conditions being localised to abnormalities at specific loci on individual chromosomes. Identification of genetic mutations allows ‘families’ of conditions to be recognised, with some common clinical and radiological features. This is reflected in the groupings in the international nosology (see Table 73.1 ) with groups including those with mutations in FGFR3 (the ‘achondroplasia’ group), or the TRPV4 group of disorders, consisting of autosomal dominant (AD) brachyolmia, metatropic dysplasia and spondylometaphyseal dysplasia, Kozlowski type (see Figs 73.5 and 73.6 ). Although classification based on genetic mutations is of value in determining an underlying causative defect, this diagnostic approach does not necessarily arrive at a precise clinical diagnosis.

With the greater accessibility of genetic testing using ‘panels’ of gene tests established in recent years for particular skeletal phenotypes, it is increasingly common for the radiologist to be presented with a child with a known genetic mutation and asked if this genetic mutation corelates with the child's imaging. Anticipatory genetic testing such as this can be not only a challenge for radiologists but also a great asset in cases where, after extensive clinical (including radiological) work-up, the diagnosis is still uncertain. Currently, National Health Service (NHS) patients in England with undiagnosed dysplasia may benefit from whole genome sequencing as part of the ‘100,000 genomes’ research project.

Because of the large number of relatively rare conditions, it is difficult or impossible for an individual radiologist to be familiar with every feature of every disorder. In addition, many of these conditions may have age-dependent features such that the radiological findings evolve or even resolve with time. For example, in Morquio disease (mucopolysaccharidosis, MPS type 4) the capital femoral epiphyses are well ossified at the age of 2 years, but at 8 years are small and flattened, and by 10 years have typically disappeared (see Fig. 73.25 ).

Each radiologist's personal experience of the individual conditions will be limited because of the vast numbers of conditions involved. Textbooks are also of limited value because of the necessarily restricted number of illustrations and obsolescence. For these reasons, skeletal dysplasias, dysostoses and malformation syndromes as a group lend themselves to computer and web-based applications. Web-based resources include those that allow individuals to refer cases to a group of experts—for example, the European Skeletal Dysplasia Network (ESDN)—or those that allow individuals to attempt to make a diagnosis themselves (e.g. the dynamic Radiological Electronic Atlas of Malformation Syndromes [dREAMS]).

A specific diagnostic label should only be attached to a patient when it is secure. An inaccurate diagnosis may have a profound effect upon the family in terms of genetic counselling, and upon the patient in terms of management and outcome. There may be a need to monitor and re-evaluate the evolution of radiological findings over time before establishing a diagnosis. A significant proportion of cases (approximately 30%) are unclassifiable because the combination of findings does not conform to any recognised condition. It is important that data, both clinical and radiological, and specimens (e.g. bone, tissue and blood) are stored to allow the diagnosis to be revisited as new research emerges. Only in this way will it be possible to ‘match’ conditions and to establish the natural history of a disorder.

Imaging

Management

Only when an accurate diagnosis has been established can the prognosis and natural history be given. For example, myopia can be corrected and retinal detachment prevented in Stickler syndrome (hereditary arthro-ophthalmopathy); cord compression can be prevented in conditions with instability of the cervical spine (see Table 73.3 ) or with progressive thoracolumbar kyphosis and spinal stenosis, as in achondroplasia.

Conditions previously considered lethal in the perinatal period can now be treated with pharmacological therapies: for example, the success of enzyme replacement therapy with asfotase alfa in selected cases of severe perinatal hypophosphatasia. Enzyme replacement therapy is also an option in mucopolysaccharidoses, where the specific enzyme deficient in each subtype is supplemented intravenously. This can improve symptoms; however, it cannot reverse already established changes.

In some conditions, cure may be achieved: for example, in the severe form of osteopetrosis (which is lethal in childhood unless treated), by means of a compatible bone marrow transplant in the first 6 months of life. Bone marrow transplantation has also been used with some success in selected patients with mucopolysaccharidoses.

Growth hormone therapy is used in selected disorders to influence final height. Growth hormone stimulates type I collagen production and is being used, in particular, to augment growth rate in children with osteogenesis imperfecta (OI) ( Table 73.4 ).

Bisphosphonates are pyrophosphate analogues that inhibit osteoclast function. They have been used in OI to improve bone density and have been used to treat bone pain and osteopenia in a variety of rheumatological and dermatological conditions. The radiological hallmark of bisphosphonate therapy, so-called ‘bisphosphonate lines’, are now well recognised ( Fig. 73.33 ).

In many conditions, orthopaedic procedures are invaluable in maintaining or improving mobility. For example, osteotomies prevent or correct dislocations or long bone bowing deformities. Patients with OI may require multiple osteotomies to correct severe deformities, as well as intramedullary rodding to reduce fractures, to maintain alignment and to provide support and stability (see Fig. 73.23 ). Joint replacements may be necessary, especially in those dysplasias (e.g. multiple epiphyseal dysplasia) in which major involvement of the epiphyses may result in premature osteoarthritis. In some conditions, limb-lengthening procedures may be appropriate to improve mobility. This is usually offered in disorders with asymmetric shortening ( Table 73.5 ), but is sometimes offered to selected patients with achondroplasia or other short-limbed dysplasias for cosmetic reasons. With the identification and localisation of specific chromosomal abnormalities associated with particular disorders, the development of gene therapy for clinical use poses many challenges and offers great potential for the future.

Genetic Counselling

When an accurate diagnosis has been made, meaningful genetic counselling can be given, both to the parents and to the affected individual. Most conditions are inherited in an AD or autosomal recessive (AR) manner . In conditions with an AD inheritance, the affected individual has a one in two chance of passing the same abnormality on to his/her offspring. However, many of these conditions arise as a spontaneous mutation, which means that the parents of the affected individual, who are themselves normal, have an extremely low risk of having another affected child . For example, although the FGFR3 mutation in achondroplasia is inherited in an AD manner, most new cases are due to spontaneous mutations . In AR conditions, both the parents are carriers of the disorder, but are not affected, and they have a one in four chance of having another affected child.

Other important, although uncommon, modes of inheritance are the result of somatic or gonadal mosaicism or uniparental disomy. Mosaicism is the presence of at least two cell lines in a single individual or tissue that derive from a single zygote. Somatic mosaicism for AD conditions results in asymmetric or patchy disorders (see Table 73.5 ). It is thought that when not a mosaic, these disorders are lethal. Clinical evidence of somatic mosaicism includes asymmetry, localised overgrowth, pigmentation and haemangiomas. In uniparental disomy, both copies of a chromosome or part of a chromosome are inherited from one parent: for example, paternal uniparental disomy 14 (patUPD14) ( Fig. 73.34 ). Imprinting refers to the situation where a gene's expression depends on the parent of origin: hence, patUPD15 leads to Angelman syndrome, while maternal UPD15 causes Prader–Willi syndrome.

Osteochondrodysplasias

The clinical and radiographic features of selected osteochondrodysplasias and dysostoses are described in Table 73.1 .

Chromosomal Disorders

45XO (Turner Syndrome)

Short stature and lymphoedema may be clinically obvious. Important radiological findings include short fourth metacarpals, a reduced angle between the distal radial and ulnar metaphyses similar to that seen in dyschondrosteosis (Madelung deformity; Figs 73.35 and 73.36 ), flattening of the medial tibial condyle with a transitory exostosis, osteoporosis, scoliosis, coarctation of the aorta, and increased occurrence of urinary tract anomalies, such as horseshoe kidneys.

Developmental Dysplasia of the Hip

This may occur as an isolated disorder (increased female incidence, breech presentation, first-born children, oligohydramnios, and when there is a positive family history) or in association with other conditions (e.g. sternomastoid tumour, torticollis, talipes calcaneovalgus, arthrogryposis multiplex and trisomy 21). The incidence in the UK approaches 1 in 400 live births, while in the USA it is 3 to 4 in 1000.

Although guidelines may vary slightly, both in the USA and the UK, US screening is performed on all newborn infants with a positive Ortolani and/or Barlow test, breech presentation or positive family history, Screening programmes for at-risk infants have led to earlier detection and treatment, and cases such as those with bilateral dislocation and formation of pseudoacetabulae are now less common. US is usually performed when the infant is about 6 weeks old. A high-frequency linear probe is used to obtain a coronal view of the hip joint, with the infant lying in a lateral position, with the hip being examined flexed and abducted. Measurements and their interpretation are summarised in Figs 73.37 and 73.38 and in Table 73.6 . The age of the infant is important when interpreting the measurements, with the difference between Graf IIa (‘immature’) and IIb hips explained by patient age being under or over 3 months. Dynamic images can also be obtained, showing the position of the femoral head under gentle stress. The various imaging appearances of developmental dysplasia of the hip (DDH) are illustrated in Fig. 73.38 .

For milder degrees of hip dysplasia, physiotherapy and/or a Pavlik harness often suffice. When ossification of the proximal femoral epiphysis renders US examination difficult (normally around 9 to 12 months of age), then radiographs are useful for follow-up and monitoring the response to treatment. Radiographs may also be required for preoperative planning in cases of more severe dysplasia. CT and MRI can be useful for assessing the position of the femoral head following operative reduction if there are ongoing clinical concerns (see Fig. 73.38 ). When it occurs, osteonecrosis secondary to surgical treatment for DDH is a relatively benign complication, not significantly affecting general physical function or quality of life.

Idiopathic Avascular Necrosis of the Femoral Head (Perthes Disease)

Osteonecrosis of the femoral head usually presents with pain or limp between 5 and 8 years of age. It is most often unilateral, but when bilateral (approximately 15%) is asymmetrical, helping to distinguish it from epiphyseal dysplasias such as Morquio disease, multiple epiphyseal dysplasia, or a late presentation of hypothyroidism. There are four stages of disease: devascularisation; collapse and fragmentation; re-ossification; and finally remodelling.

The earliest radiographic feature is that of a radiolucent subchondral fissure—the crescent sign ( Fig. 73.39 ). Disease progresses with loss of height, fragmentation and sclerosis of the femoral head (see Fig. 73.39 ). A coxa magna deformity may ensue, with lateral uncovering of the capital femoral epiphysis. There may be associated irregularity of the acetabular margin. The extent of subchondral fracture is said to be a good predictor of the final outcome. Several radiological classification systems, such as the Herring lateral pillar and (modified) Catterall systems, have been developed and shown to be reliable when used by an experienced observer.

While skeletal scintigraphy is highly sensitive and specific for detecting avascular necrosis (AVN), MRI has now largely replaced it. In those with normal signal intensity in the epiphysis, or with marked loss of signal on both T ₁ and T ₂ weighted sequences (dead bone), intravenous enhancement is not necessary. In those with more equivocal findings, intravenous contrast medium may assist in identifying areas of viable bone. Treatment options in the acute phase are largely supportive, aiming to reduce impact on the fragile femoral head. If there is significant deformity later, corrective osteotomy/leg lengthening may be considered.

Slipped Capital Femoral Epiphysis

This is the commonest hip disorder of adolescence. Anterolateral and rotational forces of the hip muscles on the femoral shaft result in anterosuperior translation of the proximal femoral metaphysis relative to the epiphysis: that is, technically it is the metaphysis rather than the epiphysis that slips ( Fig. 73.40 ). It is more common in boys, in Afro-Americans and in the obese. It most commonly occurs at the time of the pubertal growth spurt at Risser grade 0 (see Fig. 73.49 below). Slipped capital femoral epiphysis (SCFE) is extremely rare before the onset of puberty (adrenarche) and is uncommon in girls after menarche or in boys after Tanner stage 4. Bilateral slips occur in about 25% of Caucasian and up to 50% of Afro-American children. When unilateral, the left side is more often involved (65%). Endocrine disorders associated with SCFE include hypothyroidism, growth hormone deficiency, hypogonadism and panhypopituitarism.

Radiography remains the investigation of choice. The frog leg lateral is more sensitive for detection of a slipped epiphysis, and in many centres is the radiograph of choice in patients of this age presenting with hip pain. Not performing a frog leg lateral makes SCFE easier to miss, and delayed presentation/diagnosis of slips have worse outcomes. Unstable slips—where the child is unable to weight-bear on the hip—also have a higher rate of complications.

A Klein line is drawn on the AP projection while the slip angle is measured on frog lateral radiographs ( Fig. 73.41 ). Once detected, most SCFEs are fixed in situ. Complications of SCFE include chondrolysis (narrowing of the joint space), AVN and osteoarthritis.

Femoral Dysplasia (Idiopathic Coxa Vara/Proximal Focal Femoral Deficiency Spectrum)

The spectrum of femoral dysplasia encompasses all conditions from the mild idiopathic coxa vara, through moderate forms with deficiency of the proximal femur ( Fig. 73.42 ), to severe forms in which only the distal femoral condyles develop.