Congenital malformations - Edocr

308 PART VIII SKELETAL MALFORMATIONS
identified at any age. 8 The most common skeletal
dysplasias in this study were osteogenesis imperfecta,
multiple epiphyseal dysplasia, achondrogenesis,
osteopetrosis, thanatophoric dysplasia, and
achondroplasia. The prevalence rate of skeletal
dysplasias which present in the perinatal period is
reported to be about 2.1–2.3 per 10,000 births and
the rate of lethal osteochondrodysplasia is about
0.95 per 10,000 births. 7,9 However, most of these
studies concede that probably the true prevalence
was higher than captured in their databases. Prenatal
diagnosis of lethal skeletal dysplasia has
also led to an increase in termination of affected
pregnancies and a corresponding decrease in
the number of infants born with these disorders.
The most commonly reported skeletal dysplasias
and their prevalence at birth are thanatophoric
dysplasia (0.09–0.60 per 10,000 births), osteogenesis
imperfecta (0.37–0.64 per 10,000 births),
achondroplasia (0.13–0.64 per 10,000 births), and
achondrogenesis (0.23–0.64 per 10,000 births). 7,9
Other frequently observed skeletal dysplasias diagnosed
at birth include: camptomelic dysplasia,
short-rib-polydactyly syndromes type I and II,
chondrodysplasia punctata, asphyxiating thoracic
dystrophy, spondyloepiphyseal dysplasia, and
diastrophic dysplasia. 6,7 Based on a review of the
literature, Rasmussen et al reported that a specific
diagnosis could not be made in 7–21% of
all cases with osteochondrodysplasia. 7 Increased
paternal age is associated with higher risk of
achondroplasia and thanatophoric dwarfism.
Maternal use of warfarin during pregnancy has
been reported to cause clinical picture similar to
chondrodysplasia punctata. Osteogenesis imperfecta
is more common among Caucasians and
chondroectodermal dysplasia (Ellis-van Creveld
disease) has a significantly higher incidence in
the Amish population. No gender predisposition
and other risk factors have been reported.
EMBRYOLOGY/ETIOLOGY
The human skeletal system is divided into the axial
skeleton and the appendicular skeleton. The
axial skeleton includes the skull, vertebral column,
ribs, and sternum; and the appendicular skeleton
is composed of pectoral and pelvic girdles, and
the limb bones. The parts of axial skeleton, vertebrae
and ribs, originate from the somites on
both sides of the neural tube while the craniofacial
bones are of neural-crest origin. The appendicular
skeleton originates from the lateral plate
mesoderm. The earliest event in skeletal development
is the induction of undifferentiated mesenchyme
to form mesenchyme condensation
which represents the outlines of future skeletal
elements. Some bones, such as flat bones of the
skull, develop from mesenchyme by intramembranous
ossification while in most other bones
mesenchyme is first transformed into cartilage
bone models which later ossify by endochondral
ossification. The skeletal development begins at
about third week of gestation by mesenchymal
condensation and although most of the bone
growth is complete by late adolescence, the internal
reorganization of bones continues throughout
life. Skeletogenesis, the process of origin, formation,
and development of the skeleton,
requires close interaction between various regulatory
mechanisms that control cell determination
and differentiation, the orchestration of bone
and cartilage-specific genes and other modifiers,
and the influence of cell-cell and cell-matrix interactions.
10 From the embryologic perspective,
each osteochondrodysplasia is the result of an alteration
in any of these mechanisms by an abnormal
cellular product or process which in turn
results from a defective chromosome. 11 However,
there is not always a clear correlation between
genetic defect and clinical phenotypes in
all cases, indicating that other moderating factors
may be involved.
In response to the rapid accumulation of
knowledge on genes and proteins responsible
for various skeletal dysplasias, International
Working Group on Constitutional Disorders of
Bone added a classification of genetic disorders
of the skeleton which divided these disorders
into the following seven groups based on
molecular-pathogenetic etiologies: 12