Differential Diagnosis of Secondary Center of Ossification Abnormalities
Tiffany Huynh1 Moheib Ahmed1 and Waleed Kishta2*
1Department of Orthopaedic Surgery, University of Manitoba, Canada
2Department of Orthopaedic Surgery, Western University, Canada
Submission: November 17, 2016; Published: November 28, 2016
*Corresponding author: Waleed Kishta, Department of Orthopaedic Surgery, Western University, 308-1420 Beaverbrook Ave, London, ON, Canada, N6H 5W5, Tel:519-685-8021; Fax:519-685-8038; Email:firstname.lastname@example.org
How to cite this article: Tiffany H, Moheib A, Waleed K. Differential Diagnosis of Secondary Center of Ossification Abnormalities. Ortho & Rheum Open Access J. 2016; 3(5): 555617. DOI: 10.19080/OROAJ.2016.03.555621
Background: An abnormal secondary center of ossification (SCO) is a topic infrequently considered in orthopaedic literature but may result in significant morbidity and mortality in the pediatric patient. There exists a paucity of literature which may assist clinicians when assessing these uncommon pathologies.
Methods: Available literature was surveyed and the differential diagnosis of abnormal SCO was organized according to radiographic findings.
Results: This review article provides clinicians with an evidence-based quick-reference guide in approaching SCO pathologies. First, it discusses the basic anatomy and physiology of the pediatric skeleton. Secondly, it describes the basic types of irregular SCO on may encounter based on radiographic findings.
Conclusions: This discussion of SCO pathologies assists clinicians in approaching the differential diagnosis of an infrequently encountered, yet clinically significant, set of orthopaedic presentations.
The anatomy of a child’s bone may be divided into its basic components: the epiphysis, physis, metaphysis, and diaphysis. An appreciation of the growth and function of each structure is critical whenever a clinician encounters pathologies in the pediatric skeleton. The following review discusses the differential diagnoses of abnormal secondary centers of ossification (SCO), a topic which is infrequently considered in orthopaedic literature, but may result in significant morbidity and mortality in the pediatric patient. It provides the fundamental tools in approaching children with this condition in two ways: First, by surveying the basic anatomy and physiology of the pediatric skeleton. Second, by describing the basic types of irregular SCO one may encounter. The following discussion will assist clinicians in developing a practical approach towards the differential diagnoses of abnormal secondary centers of ossification.
Primary centers of ossification: During week eight of embryological development, bone arises from osteoblasts in the primary centers of ossification (PCO). In all long bones, the diaphysis is the single primary center of ossification and forms the shaft of the bone. In contrast, vertebrae and flat bones consist of multiple PCO. As a child develops, the diaphysis undergoes appositional growth with layers of periosteal membranous osseous tissue deposited over the original enchondral model. The shaft enlarges circumferentially but does not lengthen longitudinally [1-3].
The Epiphysis and the secondary center of ossification: The epiphysis flanks each end of the long bone and rests upon the physis. A joint is formed when an epiphysis articulates with an adjacent epiphysis of the bone. The epiphyseal physis lies
perpendicular to the axis of the long bone and is responsible
for longitudinal growth. In newborns, almost all epiphyses
are exclusively cartilaginous and accordingly, are not seen
on radiographs [4,5]. Secondary centers of ossification often
develop within the cartilaginous epiphysis, permitting the
epiphysis to expand globally (i.e. all directions) by enchondral
However, the number and location vary with each bone. In
most long bones, the epiphysis at each end contains a SCO but
in some, such as the phalanges and clavicles, the SCO only forms
at one end [6,7]. Sometimes, multiple epiphyseal ossification
centers form, such as in the humerus, which contains two
proximal and four distal SCO. In particular bones, one single
cartilaginous epiphysis divides into two SCO, such as with the
proximal tibial epiphysis and tibial tubercle apophysis .
The Apophysis: The apophysis is essential to bone
motion and stability as it is the attachment site f o r
musculotendinous structures. Unlike the epiphysis, it does not
usually articulate with adjacent bones and its physis lies parallel
or oblique to the axis of the long bone, so it does not contribute
to longitudinal growth. However, in flat bones, the apophyses
participate in circumferential growth and in vertebrae, elongate
the processes. The ends of particular bones function like an
epiphysis and an apophysis. Specifically, the distal humerus,
proximal ulna, proximal femur and proximal tibia are involved
both in joint movement and musculotendinous attachment
The Metaphysis: The metaphysis is the flared end of the
shaft that connects the diaphysis to the physis. Its spongy,
trabecular center is encased in a thin layer of cortical bone.
The Physis: Often referred to as simply the physis, the
primary physis rests between the epiphysis and metaphysis.
There also exist epiphyseal and apophyseal physes. These
physes share similar structures and function with its primary
Blood supply: The primary physis is an avascular structure
and is supported by branches from three blood supplies:
epiphyseal arteries, metaphyseal arteries, and periosteal
arteries from the zone of Ranvier . Branches from epiphyseal
vessels are essential for the longitudinal growth of long bones as
these vessels primarily nourish the germinal, proliferating and
columnar cell zones. Originating from the epiphyseal arteries
in the SCO, epiphyseal vessels traverse through cartilaginous
canals in the resting zone to terminate in the proliferative zone
. In the unossified epiphysis, these canals are oriented in
a parallel, longitudinal pattern but after the SCO develops, the
canals assume a radial pattern.
Branches from metaphyseal arteries have a less direct
influence on bone growth. These branches derive from periosteal vessels that penetrate the metaphysis peripherally and combine
with intermedullary blood. These vascular channels then
traverse through the gaps left by dying cartilage cells in the
zone of provisional calcification. The branches are responsible
for feeding osteoprogenitor cells and thus, the metaphyseal
branches are crucial to osteogenic and chrondrocytic cell
differentiation. Periosteal blood also flows through branches
in the zone of Ranvier to support chrondroblast differentiation.
This specialized zone contributes to circumferential growth of
the primary physis .
Growth: In long bones, growth occurs via enchondral
ossification at the physes [5,13]. The primary physis is
responsible for the majority of growth, contributing to 95%
of the bone’s length, while the secondary physis contributes
the remaining 5% . Most activity is concentrated in the
proliferative, columnar, and hypertrophic zones, where physeal
chondrocytes steadily increase in volume . Long bone length
is positively related to final chondrocyte volume and therefore,
the rate of bone growth is affected by changes in chondrocytic
activity . A similar process of chondrocyte enlargement
occurs in the epiphysis, where a much smaller physis surrounds
the SCO . However, unlike cartilage in the primary physis,
the epiphysis develops a superficial layer of cartilage that is
incapable of ossification. This layer forms articular cartilage, a
structure essential to normal joint movement.
Physeal closure: As children mature, bone growth
eventually ends with closure of the physis. The various physes
of the body close at different times depending on their locations,
however the process is similar throughout. Initially, there is a
decrease in the number of chondrocytes in the germinal and
proliferating zones. There is also a decrease in the number of
vacuolated cells in the zone of hypertrophy. The physis thins as
cartilage is steadily replaced by bone while capillary tufts from
the metaphysis grow towards the SCO. Eventually, all that is left
of the physis is the epiphyseal scar, a thin transverse line which
may be seen radiographically .
Stippled center of ossification: A heterogenous group of
skeletal dysplasias are characterized by calcific stippling of the
epiphyses. Patterns and disease prognosis vary according to the
type of dysplasia [18,19]. In the potentially lethal rhizomelic-type
of chondrodysplasia puncta, calcifications are symmetrically
distributed in the proximal humerus and femur . Affected
children who survive beyond infancy will experience resolution
of physeal stippling; however, there will remain severe lifelong
epiphyseal abnormalities . In the Conradi-Hünermann type
of chondrodysplasia puncta, there is an asymmetric distribution
of calcific deposits at the ends of long bones, vertebral processes,
carpal and tarsal bones, and ischiopubic bones. Upon resolution
of the stippling, children have less severe epiphyseal changes
than those with rhizomelic-type. Thus, assessment of the pattern and distribution of epiphyseal stippling is crucial in evaluating
the differential diagnoses and prognosis (Table 1).
Hypoplastic, Dysplastic, Dysgenetic Centers of Ossification: An abnormal appearing epiphysis may be described
as hypoplastic, dysplastic, and/or dysgenetic. Hypoplastic
epiphyses are undersized or form later than normal. Dysplastic
epiphyses appear irregular, and dysgenetic epiphyses result
from defective development. The occurrence of such epiphyseal
abnormalities may be explained by a number of causes (Table
2). Since epiphyseal ossification corresponds with skeletal growth, epiphyseal hypoplasia may be a normal physiologic
indicator of delayed bone maturation. Asymmetrically sized
epiphyses may also be normal in the growing child. However, in
the context of an isolated hypoplastic epiphysis, the differential
diagnosis includes trauma and infection . Several systemic
disorders may result in generalized epiphyseal hypoplasia,
dysplasia and dysgenesis. Often, the primary defect is abnormal
development of physeal cartilage and SCO. In some children,
the number or arrangement of chondrocytes may be affected.
In others, there may be excessive matrix formation or areas of
matrix degeneration. These abnormalities result in delayed
epiphyseal ossification and epiphyses that may appear flattened
and fragmented .
Hyperplastic center of ossification: Children may present with large epiphyses, either localized to specific sites or
generalized throughout the skeleton. In dysplasia epiphysealis
hemimelica, or Trevor disease, affected epiphyses are enlarged
due to cartilaginous overgrowth. It typically affects males, between
the ages of 2-14 years old . On radiographs, multiple foci of
ossification may be visualized medial or lateral to the affected
epiphysis. As its name suggests, there is hemimelic distribution
of the abnormal growth with respect to the epiphysis, typically
on the medial side. With time, an irregular epiphyseal bone
mass forms, which leads to limb malalignment and precocious
osteoarthritis. In infantile multisystem inflammatory disease,
there is generalized distribution of enlarged epiphyses .
Affected children develop periostitis and osteoporosis. Given
the significant long-term sequelae, it is essential to diagnose
presentations of enlarged epiphyses (Table 3).
Aseptic Necrosis of the Secondary Center of Ossification: The epiphysis and its ossification center is sustained by a limited
blood supply. This area is thus particularly vulnerable to ischemic
necrosis when its vasculature is compromised. Most children
present with isolated, unilateral involvement, although they may
also be affected bilaterally or at multiple sites. The differential
diagnoses may be divided into primary and secondary etiologies.
An example of primary osteonecrosis is Legg-Calvè-Perthes
disease, which affects the proximal femoral epiphysis in children.
Secondary processes, such as Kienböck disease of the lunate, are
precipitated by traumatic events . Family history is relevant
when assessing a child with osteonecrosis as some disorders
suggest autosomal dominant inheritance, despite trauma often
being a causative factor [27,28].
Radiographically, the process of epiphyseal ischemic
necrosis is similar among the different disorders, regardless of
their pathogenesis and anatomic site. During the initial phase of cellular death, no radiographic changes are seen. Then, a
radiolucent area surrounds the focus of necrosis and represents
osteoporotic bone undergoing osteoclastic resorption. The
necrotic area becomes radiodense as it develops a reactive
interface with surrounding tissue. As the reactive interface
remodels, the radiodense focus is bounded by a radiolucent
edge, representing osteoclastic resorption of the interface.
Meanwhile, the area surrounding the necrotic focus and reactive
interface undergoes osteoblastic bone formation and appears
relatively dense. Finally, the epiphysis becomes fragmented and
the articular surface appears flattened as it collapses .
Precocious ossification and multiple ossification centers: Advanced bone maturation is a characteristic finding in several
osteochondral dysplasias. Patients with Larsen syndrome, a
primarily autosomal dominant disorder, experience ligamentous
hyperlaxity and multiple joint dislocations. On ultrasonography,
a capital femoral ossific nucleus may be found in children with Larsen syndrome as early as six days old, whereas unaffected
children usually develop this site after three months old. On
radiographs, advanced bone age and unique accessory SCO, such
as in the calcaneus, are visible . Children with Desbeqious
dysplasia, an autosomal recessive disorder, also demonstrate
precocious ossification, possibly years in advance of their peers.
Unique SCO are often seen in radiographs of the metacarpals and
phalanges. In summary, the presence of precocious ossification
and accessory SCO may be suggestive of osteochondral dysplasias
There are more than 50 diagnoses in which either rickets
or osteomalacia are prominent features . However, there are significantly less diseases in which both are simultaneously
present (Table 4). Rickets describes deficient mineralization of
the physis, specifically at the zone of provisional calcification.
Osteomalacia refers to inadequate calcium hydroxyapatite
deposition on bone matrix . Before complete ossification
of the physis, both rickets and osteomalacia may coexist.
Characteristic radiographic findings are seen in children with
rickets, particularly in the physes of the tibia, distal femur,
proximal humerus, distal radius, and distal ulna. There may be
metaphyseal cupping and fraying, as well as bone rarefaction.
The physis appears widened, irregular, and hypodense. In the
context of osteomalacia, the appearance of rachitic growth
plates may aid in narrowing the differential diagnoses.
Chondroblastomas: Chondroblastomas are rare, benign
tumors that predominantly affect the epiphysis or apophysis of
long bones. These tumors comprise of less than 1% of primary
bone tumors and 9% of benign bone tumors. Such growths are
thought to develop from chondroblasts in the epiphyseal SCO,
most commonly affecting the femur, humerus, and tibia. On radiographs, chondroblastomas appear as well-defined lucent
lesions with central calcifications. Margins are smooth or
lobulated, and the lesion is surrounded by a thin sclerotic rim
(Figures 1-6). A third of patients demonstrate joint effusion
. Atypical features include extension of the tumor into the
metaphysis or soft tissues [37-46]. When radiographs lack
typical findings and appear nonspecific, chondroblastomas may
be confused with other epiphyseal lesions (Table 5).
Secondary center of ossification abnormalities comprise an
extensive assortment of complex and uncommon pathologies,
which may initially be overwhelming for many clinicians. As
highlighted in this review, irregular SCO may be divided into
several types, based on shared and easily identifiable features.
The radiographs included emphasize the unique features of each
type, while the tables describe radiographic findings of possible
diagnoses within each group. Knowledge provided within
this review provides clinicians with an evidence-based quickreference
guide to approaching a field of orthopaedics that is
not often encountered; but may cause significant morbidity and