eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Skeletal Dysplasia: Differential Diagnoses & Workup

Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center
Contributor Information and Disclosures

Updated: Sep 14, 2009

Differential Diagnoses

Other Problems to Be Considered

• Cardiopulmonary disorders, such as dysgammaglobulinemia, familial dysautonomia, severe recurrent pneumonias with bronchiectasis or with intractable asthma and congenital heart defects, especially cyanotic forms
• Chromosomal disorders
• Endocrine disorders, such as pituitary skeletal dysplasia, growth hormone deficiency, Mauriac syndrome, and Shwachman syndrome
• Inborn errors of metabolism, such as lysosomal storage disorders
• Intrauterine growth retardation, such as maternal insufficiency due to drugs, ethanol, infections including rubella, cytomegalic inclusion disease, syphilis, and toxoplasmosis; fetal insufficiency due to chromosomal disorders; and placental insufficiency
• Nutritional disorders due to inadequate energy intake, such as cleft palate, anorexia, deprivation, feeding problems, and severe malnutrition such as kwashiorkor or marasmus
• Primary growth disturbances, such as primordial skeletal dysplasia, Seckel syndrome, and Weill-Marchesani syndrome

Workup

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 probably include the skull (anteroposterior [AP], lateral, and Towne views), chest (AP), spine (AP and lateral), pelvis (AP), tubular bones (AP), and/or hands and feet (AP). Findings associated with particular conditions include the following:
  • 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
  • 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
  • Rib shortening - Short-rib polydactyly syndromes, asphyxiating thoracic dysplasia, chondroectodermal dysplasia, metaphyseal dysplasia (associated with immune defect), and metatrophic dysplasia
  • Absence of calcification of vertebral bodies - Achondrogenesis types I and II
  • Severe platyspondylia - Metatrophic dysplasia, lethal perinatal osteogenesis imperfecta, thanatophoric dysplasia, short-rib polydactyly syndromes, SED congenita, other types of SED, and Kniest dysplasia
  • Abnormal pelvic configuration (small sacrosciatic notches) - Achondroplasia, Ellis-van Creveld syndrome, metatrophic dysplasia, thanatophoric dysplasia, and Jeune syndrome
  • Severe hypoplasia of the scapula - Camptomelic dysplasia and Antley-Bixler 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,¹⁶ which has a sensitivity of about 60%.¹⁷
  • 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.¹⁸
  • 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.¹⁹
  • 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.
• Typical prenatal ultrasonographic features of skeletal dysplasias include the following:²⁰
  • Thanatophoric dysplasia
    • 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
    • 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
    • Asymmetric micromelia
    • Irregular/thickened bones
    • Angulated bones
    • Beaded ribs, small thorax
    • Poorly ossified skull
  • Osteogenesis imperfecta IIB
    • Lower extremities more affected
    • Less beading of ribs
    • Poorly ossified skeleton
  • Osteogenesis imperfecta IIC
    • Thin bones, multiple fractures
    • Thin beaded ribs
    • Poorly ossified skull
  • Achondroplasia
    • Rhizomelia, mild mesomelia
    • Stubby fingers
    • Frontal bossing
    • Narrowed interpediculate distance
• Common abnormal prenatal ultrasonographic findings and differential diagnoses of skeletal dysplasias include the following:²¹
  • Poor mineralization of the calvaria
    • Achondrogenesis IA
    • Cleidocranial dysplasia
    • Hypophosphatasia
    • Osteogenesis imperfecta II
  • Fractures of long bones (particularly femora)
    • Hypophosphatasia
    • Neurofibromatosis
    • Osteogenesis imperfecta II and III
  • Bent/bowed bones by ultrasound
    • 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
    • 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.¹⁹

Other Tests

• Sleep studies should be performed if a history of sleep apnea is noted.
• Molecular analyses are available in many skeletal dysplasias. Examples include the following:
  • FGFR mutation analysis in patients with achondroplasia, hypochondroplasia, thanatophoric dysplasia, and craniosynostosis syndromes (Apert, Crouzon, Pfeiffer, Jackson-Weiss, and Beare-Stevenson syndromes)
  • Mutational analysis of SOX9 in patients with camptomelic dysplasia and Antley-Bixler syndrome
• Cytogenetic study findings include the following:
  • Abnormal radiographic features may be found in certain chromosomal anomalies such as cervical hypoplasia in del(4p) syndrome.
  • Sex reversal (female external genitalia with a male karyotype, 46,XY) may be observed in camptomelic dysplasia.

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.

• Search for CME/CE on This Topic »

• Thanatophoric Dysplasia (Pediatrics: Genetics and Metabolic Disease)
• Mucopolysaccharidosis Type II (Pediatrics: Genetics and Metabolic Disease)
• Spondyloepiphyseal Dysplasia (Orthopedic Surgery)
• Growth Failure (Pediatrics: General Medicine)

• Pyle-type Metaphyseal Dysplasia
• He Walks Funny
• Fetal Loss: Addressing the Evaluation and Supporting the Emotional Needs of Parents