Skeletal Dysplasia Workup

Updated: Sep 22, 2022
  • Author: Santina A Zanelli, MD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
  • Print

Approach Considerations

Diagnosis is based on family history and physical and radiographic findings, as well as genetic testing.


Laboratory Studies

In general, clinical laboratory examinations in skeletal dysplasia are more helpful in patients with proportionate growth than in patients with disproportionate growth. Immune function, alkaline phosphatase, urinary phosphorylethanolamine, urinary mucopolysaccharides, lysosomal enzymes, and other assays may be indicated.

  • Immune function studies

    • T-cell dysfunction–related susceptibility to severe varicella infection may be seen in cartilage-hair hypoplasia (metaphyseal dysplasia, McKusick type).

    • Neutropenia is a feature of Shwachman syndrome (metaphyseal dysplasia and pancreatic insufficiency).

    • Adenosine deaminase deficiency and severe combined immune deficiency may be present.

  • Biochemical studies

    • Decreased serum alkaline phosphatase and increased urinary phosphorylethanolamine levels may indicate severe congenital hypophosphatasia.

    • Deficiency of a specific lysosomal enzyme may detect lysosomal storage disease.

    • An abnormal pattern of excretion of urinary glycosaminoglycan may indicate Kniest dysplasia (keratan sulfate), pseudoachondroplasia, and thanatophoric dysplasia.


Imaging Studies


Conventional radiographic examination remains the most useful means of studying the dysplastic skeleton. The skeletal survey should include the skull (anteroposterior [AP], lateral views), chest (AP), spine (AP and lateral views including dedicated lateral view of the cervical spine), pelvis (AP), tubular bones (AP), and/or hands and feet (AP). [11]

Skull findings are as follows:

  • Cranial sutures for evidence of craniosynostoses and presence of intersutural or Wormian bones in the lambdoid sutures

  • Overall skull mineralization, thickness of the calvarium, and craniofacial proportions evaluated for evidence of frontal bossing, midface hypoplasia, mandibular hypoplasia, and retrognathia

  • Shape of the sella turcica - Flattening of the anterior margin of the sella on the lateral view (J-shaped sella) can represent a normal variant or can be seen with space-occupying lesions of the sella or with certain dysplasias such as the mucopolysaccharidoses

Chest findings are as follows:

  • Assessment of the number, shape (shortened, thickened, or gracile appearance), and morphology (fusions) of the ribs

  • Scapular hypoplasia and clavicular absence or hypoplasia - This is seen with certain dysplasias, most notably with cleidocranial dysplasia; severe hypoplasia of the scapula is seen in camptomelic dysplasia and Antley-Bixler syndrome

  • Cardiac silhouette and lungs evaluated for congenital heart disease seen with several syndromes and dysplasias, such as Holt-Oram syndrome and Ellis-van Creveld syndrome

  • Rib shortening - Short-rib polydactyly syndromes, asphyxiating thoracic dysplasia, chondroectodermal dysplasia, metaphyseal dysplasia (associated with immune defect), and metatrophic dysplasia

Spine findings are as follows:

  • AP view to evaluate right or left convex curvature (scoliosis)

  • Lateral view to evaluate dorsal convex curvature (kyphosis or gibbus deformity) or accentuated lordotic curvature

  • Cervical spine to evaluate ossification and shape of the dens for odontoid dysplasia and cervical instability, which may be observed in several dysplasias such as mucopolysaccharidoses, spondyloepiphyseal dysplasia congenita, pseudoachondroplasia, metatropic dysplasia, and diastrophic dysplasia [26, 27]

  • Platyspondyly (flattening of the vertebral body) – (1) Without associated epiphyseal or metaphyseal abnormalities; (2) with associated epiphyseal or metaphyseal abnormalities (Severe platyspondylia may be observed in metatrophic dysplasia, lethal perinatal osteogenesis imperfecta, thanatophoric dysplasia, short-rib polydactyly syndromes, SED congenita, other types of SED, and Kniest dysplasia.)

  • Coronal clefting (vertical lucency within the vertebral body on the lateral view) can be observed in Kniest, metatropic, and Desbuquois dysplasia)

  • Narrowing of the interpediculate distance caudally on the AP view (suggests spinal stenosis), with a corollary finding of shortened pedicles on the lateral view, suggests achondroplasia and diastrophic dysplasia.

  • Posterior scalloping of vertebral bodies, endplate irregularity, anterior beaking of vertebral bodies, anterior and posterior wedging of vertebral bodies, and tall vertebral bodies are also seen in the skeletal dysplasias

  • Fusion and segmentation anomalies - More characteristic of syndromes such as Klippel-Feil or VACTERYL, as they are disorders of organogenesis

  • Absence of calcification of vertebral bodies - Achondrogenesis types I and II

Pelvis findings are as follows:

  • Absence or delay of ossification of the pubic bone in association with poor ossification of other parts of the skeleton in the neonate is seen in cleidocranial dysplasia

  • Misshapen iliac bones and short and wide iliac bones with narrow sacrosciatic notches - Commonly seen in thanatophoric dysplasia, achondroplasia

  • Abnormal pelvic configuration (small sacrosciatic notches) - Achondroplasia, Ellis-van Creveld syndrome, metatrophic dysplasia, thanatophoric dysplasia, and Jeune syndrome

  • A flat or steep appearance or presence of marginal irregularity - Seen in Jeune syndrome

Extremity findings are as follows:

  • Disproportional shortening should be evaluated for rhizomelia (relative shortening of the proximal extremities: humerus, femur), mesomelia (relative shortening of the middle portions of the extremities: radius, ulna, tibia, fibula), acromelia (relative shortening of the distal extremities), acromesomelia, and micromelia (generalized shortening of all extremities)

  • Oval translucent area in proximal femora and humeri - Achondroplasia

  • Dumbbell-shaped appearance of long bones - Kniest dysplasia and metatrophic dysplasia

  • Bowing of limbs (camptomelia) - Camptomelic dysplasia, osteogenesis imperfecta syndromes, and thanatophoric dysplasia

  • Calcified projections (spikes) at lateral femoral metaphyses - Thanatophoric dysplasia and achondrogenesis types I and II

  • Cupping of the ends of the rib and long bones and metaphyseal flaring - Achondroplasia, metaphyseal dysplasias, asphyxiating thoracic dysplasia, and chondroectodermal dysplasia

  • Long bone fractures - Osteogenesis imperfecta syndromes, hypophosphatasia, osteopetrosis, and achondrogenesis type I (Parenti-Fraccaro syndrome)

  • Absence of epiphyseal ossification centers - SED congenita, multiple epiphyseal dysplasia, and other SED (unspecified)

  • Cone-shaped epiphyses - Acrodysostosis, cleidocranial dysplasia, and trichorhinophalangeal dysplasia

  • Proximal pointing of the metacarpals - dysostosis multiplex

  • Stippling of the epiphyses - Chondrodysplasia punctata and other nonskeletal dysplasia syndromes, such as cerebrohepatorenal syndromes, warfarin-related embryopathy, chromosomal trisomy (trisomy 21, trisomy 18), lysosomal storage diseases (generalized gangliosidosis), phenytoin-induced embryopathy, Smith-Lemli-Opitz syndrome, anencephaly, cretinism, multiple epiphyseal dysplasia, SED, and normal variant hypoparathyroidism

  • Polydactyly - Short rib polydactyly syndrome

  • Duplicated calcaneus - Larsen syndrome

CT scan and MRI

CT scan and MRI of the skull and brain can reveal concurrent brain anomalies. Three-dimensional (3D) images can be used to evaluate craniofacial anomalies and deformities of the chondrocranium and cranial vault secondary to craniosynostosis and other skeletal dysplasias. These 3D architectural data are essential for reconstructive cosmetic surgery.

MRI of the spine is important to assess atlantoaxial instability seen in metatrophic skeletal dysplasia, Kniest dysplasia, certain mucopolysaccharidoses, multiple epiphyseal dysplasia, SED, cartilage-hair hypoplasia, and achondroplasia. Radiography, CT scan, and MRI findings can reveal stenosis of the foramen magnum and narrowing of the upper cervical spinal canal, which can produce severe hypotonia and spinal cord compression symptoms. MRI scans also can reveal edema and gliosis of the cervicomedullary cord secondary to the bony compression and other compression myelopathies resulting from progressive spinal deformities and scoliosis.

CT 3D reconstruction allows better surgical planning for osteotomies for complex pelvic and hip dysplasias.

Prenatal ultrasonography

Recently, noninvasive ultrasonography has gained acceptance in diagnosing fetal skeletal dysplasia. Prenatal diagnosis of skeletal diagnosis is usually made in women who previously delivered an infant with skeletal dysplasia or in whom findings of shortened, bowed, or anomalous extremities or other skeletal anomalies were depicted during routine prenatal ultrasonographic examination. For mothers who present with accurate gestational age, nomograms are available for assessing upper and lower limbs of the fetus. For mothers who present with uncertain gestational age, comparisons between limb dimensions and the head perimeter of the fetus can be used. Repeat ultrasonography examinations are usually required.

Prenatal diagnosis of skeletal dysplasia is often difficult, especially in the absence of family history. Currently, the technique used for the prenatal detection of these abnormalities is 2-dimensional (2D) ultrasonography, [28] which has a sensitivity of about 60%. [29]

Three-dimensional ultrasonography has been reported to have a somewhat better sensitivity compared with 2D ultrasonography and to be particularly useful for the evaluation of facial dysmorphism and anomalies involving the hands and feet. [30]

After 30 weeks’ gestation, standard orthogonal radiography of the maternal abdomen may help visualize the fetal skeleton and identify possible abnormalities in bone shape and size. However, superposition of fetal and maternal bones often makes it difficult to precisely visualize the fetal skeleton. [31]

Evaluation of long bones may be helpful. Measurements of all extremities can help detect predominant shortened segments, hypoplasia or absence of certain bones, degree of mineralization, bowing, angulation, and fractures or thickening secondary to callus formation.

Evaluation of short-limb dysplasia may reveal rhizomelic skeletal dysplasia (heterozygous achondroplasia, chondrodysplasia punctata), mild micromelic dysplasia (Jeune syndrome, Ellis-van Creveld syndrome, diastrophic dysplasia), mild bowed micromelic dysplasia (camptomelic dysplasia, osteogenesis imperfecta type III), or severe micromelic dysplasia (homozygous achondroplasia, thanatophoric dysplasia, osteogenesis imperfecta type II, achondrogenesis, congenital lethal form of hypophosphatasia, and short-rib polydactyly syndromes).

Evaluation of thoracic dimensions may reveal hypoplastic thorax, which is associated with severe or lethal skeletal dysplasias. This leads to pulmonary hypoplasia and is a frequent cause of death in patients with these conditions.

Evaluation of fetal ribs may reveal abnormal number which can be incidental or can be often associated with minor congenital anomalies and only occasionally with a severe malformation (Poland syndrome, VATER association, cleidocranial dysplasia, and camptomelic dysplasia, scoliosis, segmentation anomalies of the vertebrae, and abnormal karyotypes).

Evaluation of the fetal spine includes assessing the degree of ossification, hemivertebrae, scoliosis, gross vertebral disorganization, and platyspondylia.

Evaluation of hands and feet can reveal polydactyly, missing digits, and postural deformities including clubfoot and hypoplastic or hitchhiker thumbs.

Evaluation of fetal craniofacial structures can reveal defects of membranous ossification, orbits (evaluate to exclude ocular hypertelorism), retrognathia/micrognathia, facial or lip clefting, frontal bossing, and cloverleaf skull deformity.

Evaluation of fetal movement may be helpful. Movement is usually decreased in fetuses with bone dysplasias, especially lethal types.

Evaluation of associated anomalies includes maternal hydramnios, fetal hydrops, increased nuchal translucency thickness, and other fetal anomalies, such as congenital heart defects and cystic renal malformation.

The prenatal diagnosis of skeletal dysplasia is often initiated by the ultrasonographic findings in the mid trimester of a short femoral length, or by the knowledge of a previous familial history of skeletal dysplasia. Ultrasonography is highly specific for predicting lethal outcome, but of limited value for providing an accurate diagnosis of the bone disorder.

A study by Weaver et al indicated that in fetuses diagnosed with skeletal dysplasia, the risk of death from pulmonary hypoplasia can be predicted using the ratio of observed lung volume to expected lung volume (O/E lung volume) and the ratio of femur length to abdominal circumference (FL/AC). The study involved 23 pregnancies, in which magnetic resonance imaging (MRI) had been performed and ultrasonographic biometry data had been acquired. The results suggested that cutoff points for the O/E lung volume and FL/AC of 47.9% and 0.124, respectively, could be useful in predicting the lethality of pulmonary hypoplasia. [32]

Another study, by Nelson et al, indicated that in fetuses with skeletal dysplasia, the presence of the lethal form of the condition can be predicted in those with both hydramnios and an FL/AC ratio of less than 0.16. The study involved 45 fetuses with suspected skeletal dysplasia. [33]

Typical prenatal ultrasonographic features of skeletal dysplasias [34]

Thanatophoric dysplasia can indicate the following:

  • Polyhydramnios

  • Thickened soft tissues

  • Micromelia

  • Extremities at 90° to trunk

  • Bowed femur (telephone receiver)

  • Platyspondyly

  • Frontal bossing, depressed nasal bridge

  • Cloverleaf skull (type II)

Achondrogenesis can indicate the following:

  • Polyhydramnios

  • Thickened soft tissues

  • Micromelia

  • Absent ossification of vertebral bodies

  • Normal calvarial ossification (type II)

  • Small thorax, some with rib fractures (type IA)

Osteogenesis imperfecta IIA can indicate the following:

  • Asymmetric micromelia

  • Irregular/thickened bones

  • Angulated bones

  • Beaded ribs, small thorax

  • Poorly ossified skull

Osteogenesis imperfecta IIB can indicate the following:

  • Lower extremities more affected

  • Less beading of ribs

  • Poorly ossified skeleton

Osteogenesis imperfecta IIC can indicate the following:

  • Thin bones, multiple fractures

  • Thin beaded ribs

  • Poorly ossified skull

Achondroplasia can indicate the following:

  • Rhizomelia, mild mesomelia

  • Stubby fingers

  • Frontal bossing

  • Narrowed interpediculate distance

Common abnormal prenatal ultrasonographic findings and differential diagnoses of skeletal dysplasias [35]

Poor mineralization of the calvaria can indicate the following:

  • Achondrogenesis IA

  • Cleidocranial dysplasia

  • Hypophosphatasia

  • Osteogenesis imperfecta II

Fractures of long bones (particularly femora) can indicate the following:

  • Hypophosphatasia

  • Neurofibromatosis

  • Osteogenesis imperfecta II and III

Bent/bowed bones by ultrasound can indicate the following:

  • Achondrogenesis I and II

  • Antley-Bixler syndrome

  • Atelosteogenesis I, II, and III

  • Campomelic dysplasia

  • Diastrophic dysplasia

  • Hypophosphatasia

  • Osteogenesis II and III

  • Short-rib polydactyly syndrome I, II, III, and IV

  • Stuve-Wiedemann syndrome

  • Thanatophoric dysplasia I and II

Poor mineralization of the vertebrae can indicate the following:

  • Achondrogenesis IA, IB, and II

  • Atelosteogenesis I

Antenatal radiography has been used selectively when ultrasonography examinations cannot help establish a diagnosis or treatment plan adequately. Fetal radiography is especially helpful in obtaining more information about bone shape and mineralization, as well as confirming the diagnosis obtained by ultrasonography, particularly when termination of pregnancy is considered.

A babygram (AP and lateral views of an entire neonate to detect developmental anomalies of the entire skeletal system) should be performed on any infant with possible skeletal dysplasia because skeletal findings can provide essential diagnostic information needed for further genetic counseling. In addition, a babygram obtains information when consent for autopsy has been denied.

Amniography is used only occasionally to delineate fetal limbs.

Fetoscopy may be indicated in selected patients to allow direct depiction of structural defects such as limb shortening, polydactyly, facial cleft, or skin lesions.

Three-dimensional CT scanning is more precise in depicting the morphology of the spine (vertebral body shape) and pelvic bones, and in detecting bone synostosis. These abnormalities are often inconspicuous on ultrasonography but may be of great importance in establishing a precise diagnosis. However, 3-dimensional CT scanning is currently not sufficiently accurate for the analysis of metaphyseal deformities and for the assessment of bone density. [31]


Other Tests

Genetic testing plays a critical role in the diagnosis and management of skeletal dysplasias. Molecular diagnostic techniques have led to the identification of the underlying gene disorders in about two thirds of known skeletal dysplasias. Some of the more common include:

  • FGFR3 (fibroblast growth factor 3)mutations - These lead to multiple disorders, with a range of severities, from achondroplasia and hypochondroplasia to thanatophoric dysplasias

  • Collagen (COL1A1 and COL1A2) gene mutations - A major cause of osteogenesis imperfecta

  • Mutational analysis of SOX9 in patients with camptomelic dysplasia and Antley-Bixler syndrome

The most appropriate genetic test should be determined based on clinical suspicion and in collaboration with a pediatric geneticist.

Other useful tests include sleep studies, which should be performed if a history of sleep apnea is noted.


Histologic Findings

Histopathologic and electron microscopic examinations of chondro-osseous tissue may be helpful in delineating a particular skeletal dysplasia.

  • Histologic studies of growth plates

    • Cytoplasmic inclusions in resting chondrocytes reveal type I achondrogenesis, Kniest dysplasia, pseudoachondroplastic SED, type III short-rib polydactyly syndrome, and SED congenita.

    • Large ballooned chondrocytes with clear cytoplasm and markedly deficient cartilaginous matrix reveal type II achondrogenesis.

    • Resting cartilage with myxoid degeneration (Swiss cheese cartilage) may indicate Kniest dysplasia.