Idiopathic and Heritable Disorders

Pattern formation is the process by which spatial and
temporal arrangements of cell activities are organized within the
embryo so that a well-defined structure develops. Pattern formation is
critical for the proper development of every part of the organism. In
the developing limb, for example, pattern formation enables the cells
to know whether to make the upper arm or the fingers, and where the
muscles should form.

Pattern formation in many animals is based on a
mechanism where the cells first acquire a positional identity, which
determines their future behavior. The ability of cells to sense their
relative positions within a limited population of cells and to
differentiate according to this position has been the subject of
intense research. Interestingly, pattern formation in many systems has
similar principles, and more striking, similar genes. It is essentially
pattern formation—the size, shape, number, and arrangement of the
bones—that makes human beings different from rabbits or chimpanzees.

Cell differentiation is the process by which cells
become structurally and functionally different from each other, ending
up as distinct types as osteoblasts, chondrocytes, or muscle cells.
Because each cell of the organism has the same genetic material, the
achievement and persistence of the differentiation state depends on a
series of signals that ultimately control the transcription of specific
genes. In humans, the zygote gives rise to about 250 clearly
distinguishable cell types.

In any organism, differentiation leads to the production
of a finite number of discrete kinds of cells, each with its peculiar
repertory of biochemical activities and possible morphological
configurations. When cells achieve a distinctive state of

differentiation,
they do not transform into cells of another type. Differentiation leads
to a stable, irreversible set of cellular activities.

Mutations in early patterning genes cause disorders
called dysostoses: these disorders affect only specific skeletal
elements, leaving the rest of the skeleton largely unaffected. In
contrast, mutations in genes that are involved primarily in cell
differentiation cause disorders called osteochondrodysplasias, which
affect the development and growth of most skeletal elements in a
generalized fashion. Many genes have important functions in both of
these processes so that some inherited disorders can display features
of both dysostoses and osteochondrodysplasias. Genes used during
skeletal development may also be important in other organs so that when
mutated, the resulting skeletal defects are part of a syndrome.

Congenital femoral deficiencies vary in severity ranging
from hypoplastic femur, congenital coxa vara, congenital short femur
with coxa vara, and proximal femoral focal deficiency (PFFD). This
later term represents a severe disturbance in the growth of the femur
with significant shortening, abnormality of the hip, and it is commonly
associated to fibular deficiency. The cause is unknown, but in some
cases the combination of femoral deficiency and abnormal facies is
believed to be an autosomal dominant malformation.

Aitken has classified PFFD into four classes based in
the radiographic evaluation of the femoral and hip involvement. In
class A, a femoral head is present with an adequate acetabulum, but the
femur is shortened and there is significant coxa vara. In class B, the
femoral deformities are similar, but there is no connection between the
femoral shaft and the femoral head. In class C, the deformities are
more extensive with no femoral head with results in

a
poorly developed acetabulum. Finally, class D shows no development of
the proximal femur or acetabulum, and the deformity is frequently
bilateral.

The involved extremities in all four classes have a
similar appearance and should be easily recognized. The affected site
is shortened with the foot and ankle frequently at the level of the
contralateral knee. The hip is flexed, abducted, and externally
rotated, with flexion contracture of the knee and anterior instability
secondary to absence of the cruciate ligaments (Figure 9-1).
Although the hip abductors and extensors are present, they are unable
to function properly because of the abnormal anatomy of the proximal
femur. Frequently there is an associated fibular deficiency with or
without foot deformity.

The treatment aims to compensate for the functional
limitations the patient will experience, including shortening of the
limb, hip function and its relationship to the alignment of the
extremity, the deficiency in the muscles around the hip that will
result in a significant lurch, and the instability of the knee and
foot. Therefore, there are more options and variations in the treatment
of this complex deformity than in any other congenital limb deficiency.

The choice of treatment is made by the parents and the
medical team after considering all surgical alternatives and functional
results. If the predicted leg length discrepancy is less than 20 cm at
maturity, the child may be a suitable candidate for a limb lengthening
procedure. If the discrepancy is more than 20 cm, the options are
prosthetic management with ankle disarticulation; ankle disarticulation
and knee fusion; ankle disarticulation and femoralpelvic fusion;
rotationplasty and knee fusion; and rotationplasty and femoral-pelvis
fusion.

Tibial deficiency is a rare type of congenital limb
deficiency. It is characterized by a complete or partial absence of the
tibia with bowing, limb shortening, and an intact fibula. The tibial
deficiency may have a relatively normal knee and foot (intercalary
deficiency), or it may be associated with absence of the medial portion
of the foot (terminal deficiency). The knee may present a flexion
contracture and the foot is rigidly held in varus and supination. Other
findings include shortening of the femur, polydactyly and upper
extremity abnormalities, and other organ systems (Figure 9-2A). The cause is unknown, but familial occurrences have been reported.

There are two classifications, both based on the
radiographic findings. The simplest is that of Kalamchi and Dawe. Type
I is complete absence of the tibia (Figure 9-2B).
Type II is absence of the distal tibia but with a good proximal tibial
portion. Type II is distal tibiofibular diastasis. An unusual type is
fibular dimelia in which the tibia is absent and the fibula is
duplicated.

Treatment considerations include the extent of the
tibial deficiency, the magnitude of the limb shortening, the severity
of the foot deformity, and importantly, the presence of active knee
extension, which implies an adequate active quadriceps muscle and
insertion on the tibia. Patients with a complete absence of the tibia
can be treated by knee disarticulation and prosthetic fitting.
Alternatively, the fibula can be fused to the femur to warrant an
increase in the length of the stump and to provide a longer lever arm
for the prosthesis. In patients with absence of the tibia but with a
good quadriceps mechanism, the proximal fibula can be transferred to
the femoral

notch,
which will lead to a hypertrophy of the fibula. Those patients with a
portion of the tibia present, a proximal tibiofibular fusion and
amputation of the foot with prosthetic replacement will provide an
excellent result. In cases of distal tibiofibular diastasis, a fusion
of the calcaneus to the fibula is indicated.

The terms fibular deficiency or fibular hemimelia
imply a congenital absence of all or part of the fibula, and they
encompass a spectrum of abnormalities related to abnormal growth and
development of the fibula. The precise cause of fibular deficiency is
unknown and the deformity normally occurs sporadically. The resultant
limb deficiency is usually a terminal type with associated foot
abnormalities. In addition, up to 50% of the patients experience an
associated femoral shortening that is variable in severity.

There have been numerous classifications mainly based on
the anatomic and radiographic appearance of the deformity, but most of
these classifications do not provide satisfactory guidelines for
management and they do not take in account the shortening of the limb,
one of the most significant factors when making management decisions.
Recently, Birch and collaborators have proposed a functional
classification based on the functionality of the foot and the limb
length discrepancy. However, given the large variation in the different
aspects of fibular deficiency, including parent’s expectations, any
classification only provides a general guide for management and a
method for comparison of treatment results.

The clinical deformity can vary from barely detectable
to severely affected. The typical characteristics include a valgus foot
that often has one or several rays missing. The ankle is in valgus
because of the absence of the lateral malleolus and angulation of the
distal tibia. A ball-and-socket ankle has been classically described.
In severe deficiencies, the foot is in rigid equinus (Figure 9-3A).
There is also shortening of the femur, variable anterior bowing and
shortening of the tibia, and variable valgus instability of the knee
with hypoplasia of the lateral femoral condoyle and patellar
abnormalities such as hypoplasia, patella alta, or subluxation (Figure 9-3B).

Treatment considerations are very complex and include
management of the foot deformity as well as of the limb length
discrepancy. If the foot has significant lateral deficiency and it is
rigid, then amputation (Boyd or Syme type) is generally considered.
Prosthetic fitting is then provided with excellent

results.
In patients with a plantigrade and functional foot, the limb length
discrepancy can be addressed by epiphysiodesis of the contralateral
side, femoral or tibial lengthening, or a combination of techniques.

The first transcription factor discovered to cause a
skeletal dysplasia was SOX9 in camptomelic dysplasia. It is a severe
and rare form of dysplasia that is sometime fatal. This dominantly
inherited condition is characterized by congenital bowing and
angulation of long bones (camptomelia), primarily involving the tibias
and femurs, and disproportionate short-limb stature. There is relative
macrocephaly, distinctive face (flattened face with a high forehead),
low nasal bridge, and a specific pattern of defective mineralization
including areas of the spine with progressive scoliosis. There is also
defective cartilage in the tracheal rings and lower respiratory tract
that may cause respiratory failure. Extraskeletal features include XY
sex reversal and developmental defects of the heart and kidneys.

The transcriptional targets of SOX9 include several
cartilage matrix proteins such as types II and XI collagen and
aggrecan. Hence, the skeletal manifestations are in part caused by
decreased expression of these molecules and explain some of the
phenotypic overlap with some of the severe type II collagenopathies.
The bowing of the bones appears to be due to an abnormality in the
formation of cartilage during fetal development (dischondrogenesis).

Treatment is symptomatic and directed to the
deformities. However, there is a high degree of complications such as
pseudoarthrosis and neurological complications.

Although the name suggests that only two bones are
affected, this is a true dysplasia because there are numerous
abnormalities in all parts of the skeleton, primarily those bones of
membranous origin. It is transmitted as an autosomal dominant
condition, and the defect is in the RUNX2 gene, which encodes for a
transcription factor required for osteoblasts differentiation.
Approximately two-thirds are familial and the rest are new mutations.

Typically, the disorder is identified within the first 2
years of life. Classic features include a widening of the cranium and
dysplasia of the clavicles and pelvis. The patients have mildly to
moderate short stature. There is bossing in the frontal parietal and
occipital regions. There is maxillary micrognathism and common cleft
palate and dental abnormalities. The clavicles are partially or
completely absent (10% of the time). This defect causes the shoulders
to look droopy, the chest to be narrow, and the neck longer. The defect
may be palpable. When it is bilateral, the classic diagnostic feature
is that the child can touch the shoulders together, an ability that
helped one college wrestler to escape holds. Brachial plexus irritation
occurs in rare occasions. The pelvis shows bilateral involvement with
wide symphysis. The iliac wings appear small and coxa vara may occur,
causing limitation of abduction and Trendelenburg gait. Scoliosis and
syringomyelia have been described, and it is recommended to obtain a
MRI in patients with progressive scoliosis.

There is no need for treatment for the clavicles. Coxa
vara is treated by corrective femoral osteotomies. Scoliosis should be
treated as idiopathic scoliosis. If there is brachial plexus irritation
with pain and numbness, excision of the clavicular fragments can be
performed to decompress it.

Osteogenesis imperfecta (OI) is one of the bestknown
genetic skeletal disorders. At least seven discrete types have been
described, ranging from mild disease with normal life expectancy to a
lethal form. Approximately 80 to 90% of patients have mutations in one
of the two genes encoding type I collagen (COL1A1 and COL1A2). However,
in spite of the large number of mutations already identified in OI, the
precise mechanisms by which different mutations cause different
phenotypes are not clearly understood.

Clinical features include increased bone fragility with
an increased susceptibility for fractures to occur, short stature,
laxity of ligaments, hearing loss, and depending on the subtype, blue
sclera, dentinogenesis imperfecta, respiratory insufficiency, excessive
sweating, and early bruisability. The severity of involvement ranges
from the severe cases of a crushed stillborn fetus, to an infant with
multiple or unusual fractures, to an almost symptom-free adult.

The classification that is most widely accepted is the
Sillence classification. Type I is a milder form of OI with onset of
fractures after birth (most preschool age). Fractures heal without
deformity, and their incidence decreases after puberty. Type I patients
are further divided into two subgroups based on the presence of
dentinogenesis imperfecta. Type II demonstrates more severe involvement
(dark blue sclera, concertina femurs, beaded ribs) with most infants
dying in the perinatal period. Type III develops severe progressive
deformities in the extremities and spine, and these patients usually
have in utero fractures and many die in infancy and early childhood
from respiratory insufficiency. These patients have normal sclerae and
hearing. Type IV demonstrates severe osteoporosis, bowing of the bones,
and increased susceptibility to fractures, but they lack blue sclera.
Many of these patients have short stature. The most severely affected
surviving patients often have this type of disease. Type IV patients
are also subdivided based on the presence or lack of dentinogenesis
imperfecta. Type V patients have bone fragility, but not blue sclera or
dentinogenesis imperfecta. These patients are characterized by three
distinctive features: the presence of hypertrophic callus formation at
fracture sites, calcification of the interosseous membranes between the
bones of the forearm, and the presence of a radio-opaque metaphyseal
band immediately adjacent to the growth plates on radiograph. Type VI
patients have moderate deformity, not blue sclera or dentinogenesis
imperfecta. The distinctive features of this OI type VI are the fish
scale-like appearance of the bone lamellae and the presence of
excessive osteoid upon histological examination.

Radiographically, patients with OI demonstrate
osteopenia though it varies in its severity according to the severity
of involvement. Type I patients have minimal alterations with thinning
of the cortices and decreased trabecular bone. In type II patients
there is bone shortening and widening, and they have “crumpled
concertina” appearance. Type III patients have narrow diaphyses with
increased flaring and enlargement of the metaphyses and epiphyses.
Typically the long bones are deformed due to multiple fractures. Pelvic
radiographs demonstrate protrusio acetabuli. Spine radiographs
demonstrate platyspondyly, biconcave vertebrae, and varying degrees of
scoliosis, kyphosis, or spondylolisthesis. Some patients will have
cranial osteoporosis with wormian bones and flattening of the occiput
(tam-o’-shanter skull).

There is no specific treatment to correct the basic
mutant gene defect in OI. The treatment of OI has been focused on
maximizing patient’s function,

preventing
deformity and disability as a result of recurrent fractures, correcting
deformities that have developed, and monitoring potential complicating
conditions associated with OI.

The treatment of fractures in patients with OI is
sometimes difficult. Fractures heal readily, often with exuberant
callus, but this is plastic and easily deformed. As a result, bone
deformities and shortening occur. Closed treatment is often used with
lightweight splints or braces. Devices such as the parapodium may help
a child to acquire an upright position. When conservative treatment
fails, intramedullary rodding is indicated. In addition, multiple
corrective osteotomies with intramedullary fixation have been accepted
for managing recurrent fractures (Figure 9-4). Scoliosis treatment in patients with OI still remains a challenge.

Based on recent advances in the understanding of the
underlying biology of this disorder, the medical treatment of OI is
undergoing major improvements. Two new approaches have been studied;
one using bisphosphonates and the other using bone marrow
transplantation.

Bisphosphonates are synthetic analogs of pyrophosphate
that inhibit bone resorption, therefore increasing bone mass overtime.
They have been extensively used in adults with osteoporosis, but they
have recently explored in children. Several cohort studies of patients
with OI have demonstrated improved bone mass after the administration
of intravenous pamindronate. This increase in bone mass is mainly due
to an increase in the thickness of the cortex, which resulted in a
significant reduction of fracture rates. Fracture healing was not
affected; neither was longitudinal bone growth. Patients undergoing
treatment also described less fatigue and less chronic pain, and they
had minimal side effects. Although very encouraging, many questions
still need to be resolve regarding when to start treatment, duration,
long-term efficacy, and the safety of the treatment.

The second approach has been the use of bone marrow
transplantation. Bone marrow contains nonhematopoietic mesenchymal stem
cells (MSC) that can differentiate, among other cell types, into
osteoblasts. The results are very encouraging and demonstrated good
engraftment of the cells in vivo with improvement of the osteopenic
phenotype.

Marfan syndrome is an autosomal dominant disorder that
has an estimated incidence of approximately 1 in 10,000. Approximately
25% of cases occur in the absence of a family history representing new
mutations. The syndrome involves many systems (skeletal, ocular,
cardiovascular, pulmonary, skin and integument, and dura), but its more
prominent manifestations are skeletal, ocular, and cardiovascular.
Mutations in the gene encoding type 1 fibrillin (FBN1) have been
reported in Marfan syndrome patients. Fibrillin-1 represents the major
component of microfibrils, which are found in many types of connective
tissue, including bone. To date over 500 mutations have been identified
in the FBN1 gene.

Three
categories of mutations have been described: (1) missense mutations,
(2) small insertion or deletions, mutations causing premature
termination of translation, and (3) exon-skipping mutations. Presently
no definite genotype/phenotype correlations have been identified. To
facilitate the identification of different mutations, a “Marfan
database” has been developed that includes not only molecular but also
clinical data. It is only through a large collaborative international
effort that genotype and phenotype correlations will eventually be
identified.

Although no specific therapy exists for Marfan syndrome,
it is of great importance to confirm or exclude the diagnosis in family
members at risk as early as possible because of the potential fatal
complications of the disease (aortic dissection and rupture). At
present, diagnosis for most cases is still based on thorough clinical
examination, including measurements of body proportions,
echocardiography of the aorta, slit-lamp ophthalmologic evaluation, and
radiographs. In the absence of a family history, patients are diagnosed
based on involvement of the skeletal system and two other systems with
at least two major manifestations (ectopia lentis, aortic
dilation/dissection, dural ectasia, or molecular data). In the presence
of a positive family history, an affected person should display one
major criterion in an organ system and involvement of a second system.
Within a given family, however, considerable heterogeneity may be
present. It is not uncommon for milder involved patients to have the
diagnosis go unrecognized until another family member is diagnosed. The
phenotype of the Marfan syndrome remains incompletely defined. Most
manifestations are age dependent and are difficult to quantify.
Molecular data are becoming increasingly important to better
characterize Marfan syndrome and to study its natural history.

A variety of skeletal manifestations may be present in
patients with Marfan syndrome. Most characteristic is tall stature and
disproportionately long, thin limbs (dolichostenomelia). This can be
confirmed by demonstrating a smaller than normal upper segment (head to
pubic symphysis) to lower segment (pubic symphysis to plantar surface)
ratio or an arm span that exceeds the patient’s total height by at
least 7.5 cm. Patients frequently have arachnodactyly (abnormally long
and slender digits) and ligamentous laxity. This combination of joint
laxity and long digits results in several clinical signs that are
indicative of, but not pathognomonic, for Marfan syndrome. One such
sign is the thumb sign described by Steinberg. This is positive if the
opposed thumb projects past the ulnar border of the clenched fist. The
wrist sign is the ability of the patient to encircle the opposite wrist
with the thumb and small finger, with the thumb overlapping the distal
phalanx of the small finger. The crossover leg sign is the ability of
the patient to touch the floor with the foot of the crossing-over leg.
Joint laxity is another hallmark of the disease, and many patients have
recurrent instability of the patella, shoulder, hip, and thumb. Marked
flatfeet (pes planovalgus), genu valgum, and genu recurvatum are
typical.

Approximately 66% of patients have pectus excavatum
(chest depression) or pectus carinatum (pigeon chest). The chest wall
deformities in Marfan patients are due to longitudinal overgrowth of
the ribs. A severe pectus deformity can become clinically significant
by reducing total lung capacity, forced vital capacity, and forced
expiratory volume. Additionally, the occurrence of a severe pectus
deformity in association with scoliosis may further compromise the lung
capacity of patients with Marfan syndrome. It is recommended that
patients with Marfan syndrome have repair of the pectus deformity done
after skeletal maturity to minimize the chance of recurrence with
longitudinal growth of the ribs.

Spinal deformities are a frequent finding in patients
with Marfan syndrome. Abnormalities include thoracic lordosis,
thoracolumbar kyphosis, flat-back deformity, and spondylolisthesis.
Scoliosis is one of the most common and important manifestations of
Marfan syndrome from an orthopaedic perspective with an incidence of
62%. The curve pattern frequently is either a single right thoracic
curve or a double major curve pattern. The thoracic curve is most
commonly lordoscoliotic. The thoracolumbar junction is prone to
kyphosis, probably related to the underlying ligamentous laxity. The
treatment regimen for scoliosis in Marfan syndrome and adolescent
idiopathic scoliosis is similar but the results of treatment are often
different. Specifically, scoliosis in Marfan syndrome has a higher
tendency toward progression and responds less well to bracing than
adolescent idiopathic scoliosis. Both family and physician should be
aware of these facts. In addition, back pain is frequently associated
with scoliosis in Marfan syndrome.

Bracing is recommended for curves between 15° and 25°.
Spinal fusion with autogenous bone graft and rigid internal fixation
should be considered in patients with curves that have progressed
beyond 40° (Figure 9-5A,B). The surgeon should

be aware that there is significantly smaller pedicle widths and laminar
thickness in patients with Marfan syndrome as well as widened
interpedicular distances in the lumbar spine. These osseous vertebral
anomalies may be responsible for some reported postoperative
complications including fracture dislocation and pseudarthrosis.
Preoperative cardiac evaluation is critical and frequently determines
whether a patient is a suitable candidate for extensive spine surgery.

Planovalgus foot deformity is common in Marfan syndrome
and is postulated to be due to increased ligamentous laxity resulting
from underlying connective tissue pathology. Acetabular protrusio can
be seen radiographically in as many as half of patients with Marfan
syndrome. Patients can be asymptomatic or have symptoms of hip pain and
stiffness. Because of the lack of a direct relation between protrusio
and hip symptomatology treatment recommendations are difficult to make.

Dural ectasia, a widening of the dural sac, has a
reported incidence of 63% in Marfan syndrome and can result in back
pain and headaches. It usually occurs in the most caudal portion of the
spinal column

causing
bone erosion and anterior meningoceles. Dural ectasia is thought to
result from fibrillin deficiency resulting in weakness of the dural
sac. There has been a reported direct correlation between the size of
the dural ectasia and the presence of pain. Posterior laminectomy has
been used as a means of relieving back pain thought to be secondary to
dural ectasia.

The hallmark of ocular involvement is ectopia lentis
(dislocated lens) due to lax suspensory ligaments. The dislocation is
superior and lateral and may not be recognized unless a slit-lamp
examination is performed. Ectopia lentis occurs in more than half of
involved patients. Other ocular manifestations include myopia, retina
detachments, strabismus, cataract, and glaucoma.

Multiple cardiovascular abnormalities exist in patients
with Marfan syndrome and are the most common cause of death in this
patient group. For this reason a complete cardiology workup should be
done on all Marfan syndrome patients that includes an electrocardiogram
and echocardiogram. The most serious complication is dilation of the
ascending aorta and associated aortic regurgitation. This often leads
to a dissecting aortic aneurysm. Mitral valve prolapse and mitral valve
regurgitation are the most common significant cardiac problems in
children. Many patients are being treated with medications in an
attempt to delay the onset of serious cardiovascular abnormalities.

Multiple epiphyseal dysplasia (MED) is one of the most
widely known and commonly occurring skeletal dysplasia. It is most
commonly inherited in an autosomal dominant fashion though autosomal
recessive forms have been described as well. Its prevalence is
estimated at 1 in 10,000 individuals. The predominant feature of
multiple epiphyseal dysplasia is the delayed and irregular ossification
of numerous epiphyses. In most cases there is pain and stiffness in the
joints, with hips and knees being most commonly affected. In general,
affected patients have mild short stature and early onset
osteoarthritis.

Historically, it was described as occurring in two
separate forms: Ribbing’s dysplasia, having mild involvement, and
Fairbanks dysplasia, a more severe type. However, with the current
genetic understanding, multiple epiphyseal dysplasia is now considered
to represent a continuous spectrum from mild to severe and these
eponyms have been abandoned.

Multiple epiphyseal dysplasia shows considerable genetic
heterogeneity. To date, mutations have been reported in 40 patients or
families with multiple epiphyseal dysplasia, and 15 of these are
allelic with pseudoachondroplasia and result from mutations in the gene
encoding cartilage oligomeric matrix protein (COMP). MED can also
result from mutations in the genes encoding the α1, α2, and α3 chains
of type IX collagen, COL9A1, COL9A2, COL9A3, respectively. Furthermore,
mutations in the gene encoding matrilin-3, a member of the matrilin
family of extracellular oligomeric proteins, can cause a distinctive
mild form of MED. Finally, it has been demonstrated that a form of
recessively inherited MED, with a distinctive clinical presentation
including clubfoot and bilateral double-layered patellae, can result
from mutations in the solute carrier family 26, member 2 gene
(SLC26A2). Therefore, MED is one of the more genetically heterogeneous
of the bone dysplasias.

Patients typically present in early adolescence because
of joint stiffness and contractures, lower extremity pain, angular
deformities of the knees, gait disturbance, or short stature. Depending
on the severity of the epiphyseal dysplasia, symptoms may develop as
early as 4 or 5 years. It is not uncommon, however, for patients with
milder forms to go unrecognized until young adult life. Most patients
have minimal short stature and are above the third percentile for
standing height; so true dwarfism is not present. The face and spine
are normal. There are no associated neurologic findings. Intelligence
is not affected. The epiphyses of the upper extremities can be involved
but patients rarely complain of any significant symptoms in this area.
Mild limitation of motion in the elbow, wrist, and shoulder is
occasionally found.

The principal finding on radiographs is a delay in the
appearance of the ossification centers. When the epiphyses do appear,
they are fragmented, mottled, and flattened. The more fragmentation
there is in the capital femoral epiphysis, the earlier onset of
osteoarthritis (Figure 9-6).

The proximal femur is most often affected and its
appearance may be easily confused with those of bilateral
Legg-Calvé-Perthes disease. Several radiographic clues may be helpful
in differentiating the two. In Legg-Calvé-Perthes disease, usually one
hip is involved before the other, so that each hip is in a different
stage of the disease. This is not the case in MED. In addition,
acetabular changes are primary in MED and are more pronounced.
Metaphyseal cysts are seen in Legg-Calvé-Perthes disease, but not in
MED. Radiographs of the knees, ankles,

shoulders,
and wrists should be obtained in any child when the diagnosis of
Legg-Calvé-Perthes disease is being entertained to rule out MED.

Coxa vara occurs in some patients. Radiographs of the
knees often demonstrate flattening of the femoral condyles as well as a
genu valgum deformity. Osteochondritis dessecans may be superimposed.
Lateral radiographs of the knees demonstrate a double-layered patella
in some patients. When this is present, it is characteristic for MED.
The ankles in MED are also in valgus due to deformity in the talus
predominantly. Upper extremity involvement is less severe. The
metacarpals and phalanges usually are short with irregular epiphyses.
MED is distinguished from spondyloepiphyseal dysplasia by the absence
of severe vertebral changes. Mild endplate irregularities may be
present.

Hip pain or subluxation is a common reason patients with
MED seek orthopaedic care in adolescence. Containment surgery can be
considered for those hips that show progressive subluxation. Although
the principle of coverage is the same as that used in Perthes disease,
there is often preexisting coxa vara in hips with MED, which
contraindicates use of a proximal femoral varus osteotomy. In those
cases, a shelf acetabular augmentation can improve coverage of the
misshapen femoral head. If hinge abduction is present on arthrography,
a valgus proximal femoral osteotomy may improve congruency and
therefore relieve pain. Osteotomies may be helpful in realigning
angular deformities at the knees. For optimal surgical correction, the
site of the deformity must be ascertained preoperatively as either the
distal femur, proximal tibia, or both. Degenerative joint disease is
the biggest problem, and it usually occurs in the second or third
decade. If the femoral head is well formed at maturity, the onset of
arthritis is delayed. The hip is the most common location of arthritis
in this patient group and often leads to total joint arthroplasty.

Pseudoachondroplasia is a form of short-limbed dwarfism
that has a prevalence of approximately four per million, making it one
of the more common skeletal dysplasias. It is characterized by
involvement of both the epiphyses and metaphyses with affected
individuals having significantly short stature and a predisposition to
premature osteoarthritis. The spine is also involved with this disorder.

Pseudoachondroplasia is usually transmitted as an
autosomal dominant trait. The molecular genetics of
pseudoachondroplasia have been extensively studied and it now appears
that this disease results almost exclusively from mutations in the gene
encoding cartilage oligomeric matrix protein (COMP). The COMP gene
consists of 19 exons, and the majority of mutations to date (95%) are
clustered within exons 8 to 14, which encode the type III repeats. The
fact that most of these mutations are in the conformationally sensitive
type III repeats indicates that this region is critical for protein
function. The remaining 5% of mutations are in exons 16 and 18, which
encode specific segments of the C-terminal globule.

The cell-matrix pathology of pseudoachondroplasia
resulting from COMP mutations has been well documented. Abnormal COMP
is retained within the rough endoplasmic reticulum of cartilage,
tendon, and ligament cells. This results in the secondary retention of
type IX collagen, chondroitin sulfate proteoglycan 1 (aggrecan), and
link protein. This retention of proteins leads to a reduction in the
amount of these molecules available for interactions within the
extracellular matrix of cartilage resulting in cell death and the
phenotypic picture of pseudoachondroplasia. Additional studies are
needed to delineate the mechanism leading to excessive retention of
proteins in order to develop treatment modalities.

Pseudoachondroplasia is a relatively straightforward
disease to provide molecular diagnosis for because it results almost
exclusively from mutations

along
a very compact region in the COMP gene. Molecular diagnosis for
pseudoachondroplasia is currently provided on a commercial basis
(www.genetests.com) and also as part of the service provision of the
European Skeletal Dysplasia Network (ESDN) for research and diagnosis
(www.esdn.org).

Children with pseudoachondroplasia are normal at birth
and are usually diagnosed at 2 years of age after the onset of a
waddling gait and at the time rhizomelic shortening becomes noticeable.
Adult height ranges from 106 to 130 cm. Growth curve charts specific to
pseudoachondroplasia are available. The clinical features are limited
to the skeleton. The skull and facies in pseudoachondroplasia are
normal, and this is helpful in differentiating it from achondroplasia,
in which frontal bossing and midface hypoplasia are present.
Abnormalities of the lower extremities are common and include genu
valgum and varum deformities. Some patients develop windswept deformity
of the knees, in which genu valgum is present on one side and genu
varum on the other. The joints are extremely lax, especially in
childhood and adolescence, and there is a predisposition to early
osteoarthropathy. The large weight-bearing joints (hips and knees) are
the ones most often affected, and approximately one-third of patients
need total hip replacement by their mid-30s. Scoliosis may occur in
adolescence but is generally not severe. Cervical spine instability is
seen in 10 to 20% of individuals (Figure 9-7). Development milestones and intelligence are normal and premature mortality is not a reported problem.

Typical radiographic changes include small, irregular
epiphyses and metaphyseal changes. Hand radiographs reveal delayed
epiphyseal ossification resulting in delayed bone age. In the long
bones, these changes are seen as epiphyseal ossification delay. When
the epiphyses do ossify, they appear irregular and fragmented. The hip
and knee are most severely affected (Figure 9-8).
In the pelvis, there is delay in ossification of the capital femoral
epiphysis, and when ossified they are small and flattened. The femoral
heads may resemble what is seen in other spondyloepiphyseal dysplasias
or bilateral Legg-Calve-Perthes disease. Sclerosis and irregularity of
the acetabular roof are commonly observed. Subluxation of the hips
often occurs and degenerative arthritis develops in response to the
incongruity. The vertebral changes in pseudoachondroplasia are
characteristic and consist of anterior beaking in childhood that
resolves in adolescence. The interpedicular distance in the lumbar
spine is normal in pseudoachondroplasia, unlike achondroplasia.
Odontoid hypoplasia may be present resulting in atlantoaxial
instability.

Patients with pseudoachondroplasia often have
significant angular deformities of the lower extremities that require
corrective osteotomies. Careful preoperative assessment is necessary to
properly realign the mechanical axis through the hip, knee, and ankle.
For instance, in genu varum associated with

achondroplasia,
the deformity is present solely in the tibia; however, in
pseudoachondroplasia the deformity is often present in both the femur
and the tibia, requiring osteotomies in both the distal femur and the
proximal tibia. Care must also be taken in assessing the contribution
of ligamentous laxity to the bowing deformity. After corrective
osteotomy, recurrence of the deformity with growth is not uncommon.

Premature osteoarthritis of the hip in early adulthood
is a frequent problem in pseudoachondroplasia. Patients with
symptomatic subluxation or incongruity may benefit from a realignment
osteotomy of the proximal femur. Varus osteotomy of the proximal femur
usually creates more incongruity. If hinge abduction is present,
demonstrated by the femoral head levering out of the joint with
abduction of the hip, a proximal femoral valgus osteotomy may improve
joint congruity and improve abductor function. Before performing a
proximal femoral valgus osteotomy, preoperative arthrography should be
performed to demonstrate improved congruity with 15° to 20° of flexion
and adduction of the femur. Abduction of the hip should demonstrate
hinge abduction of the femoral head. Reconstructive pelvic osteotomies,
such as the Salter osteotomy or the triple innominate osteotomy of
Steel, are contraindicated in pseudoachondroplasia because a concentric
reduction is not present preoperatively, which is a prerequisite for
these osteotomies. Salvage procedures such as the shelf augmentation or
the Chiari osteotomy can be done in select cases. As many as 50% of
adult patients have undergone total hip arthroplasty.

Achondroplasia is by far the most common
chondrodysplasia in humans, occurring in about 1 in 30,000 live births.
A single gene defect (a mutation in the FGFR3 gene) has been
established for this disorder. Initial reports, confirmed subsequently
in many other laboratories, demonstrated that more than 97% of patients
with achondroplasia carried the same mutation, a G to A change at
nucleotide 1138, and that the remaining patients had a G to C change at
the same nucleotide. Very recently it has been demonstrated that, as
previously expected, FGFR3 mutations in sporadic cases of
achondroplasia occur exclusively on the parentally derived allele.

Since the FGFR3 mutation in achondroplasia was
recognized, similar observations regarding the conserved nature of
FGFR3 mutations and resulting phenotype have been made regarding
hypochondroplasia, the lethal thanatophoric dysplasia, SADDAN (severe
achondroplasia with developmental delay and acanthosis nigricans), and
recently two craniosynostosis disorders: Muenke coronal
craniosynostosis and Crouzon syndrome with acanthosis nigricans. More
importantly, the relationship between mutations in the FGFR3 gene and
other FGFR genes, and the phenotypes that result from these mutations
have improved our understanding of these disorders, and it has been
observed that there is a highly conserved relationship between
mutations at a particular amino acid and the resulting phenotype. The
skeletal manifestations of achondroplasia are related to a defect in
endochondral bone formation. The resulting growth disturbances are
variable, affecting proximal segments to a greater extent than the
distal segments of the limbs (rhizomelia), and with relatively minor
involvement of the growth of the spine.

Achondroplasia is recognized at birth, and the
appearance of a person with achondroplasia has numerous features that
are uniform and predictable. Intelligence is normal, and life
expectancy is not significantly diminished. The predicted adult height
is 132 cm for men and 122 cm for women. Obesity is more common than in
the general population. Developmental milestones are met later in
children with achondroplasia than the averagestature children.

There is enlargement of the cranium with frontal
bossing, midface hypoplasia, flattening of the nasal bridge, and
prominent mandible. The foramen magnum is frequently narrowed and it is
associated with neurological complications from compression of the
brain stem (quadriparesis, spasticity, sleep apnea and respiratory
insufficiency, and sudden death). The spine length is in the lower
range of normal whereas the extremities are much shorter than normal,
with the proximal segments—the humeri and femora—the most foreshortened
(rhizomelic). There is kyphosis of the thoracolumbar junction during
infancy, and it usually improves with increasing age. Scoliosis is
rare. Hyperlordosis of the lumbar spine increases with age, and there
is a high incidence of symptomatic spinal stenosis (narrowing of the
interpedicular distances with shortening of the pedicles). Clinically,
patients will present with low back and leg pain, paresthesias,
dysesthesias, weakness, or bowel and bladder incontinence.

There is limitation of extension of the elbows and some
patients may have asymptomatic radial head dislocations. Patients have
a classic “trident hand” characterized by a persistent space between
the long and ring fingers. The main functional limitations of the upper
extremities are related to shortening of the humeri, which lead to
difficulties in personal hygiene and dressing. Radiographically, the
pelvis is broad with a diminished vertical height. The iliac crest has
a square appearance and the superior acetabular roof is horizontal.
There is flaring of the distal femoral metaphysis. Genu varum is very
common, with ligamentous laxity and the fibula overgrow the tibia.
Internal tibial torsion is common with varus of the ankle (Figure 9-9).

Children with achondroplasia should be closely monitored
in the first 2 years of life for signs of foramen magnum stenosis. If
the diagnosis is made and symptoms are persistent, decompression of the
brain stem is indicated. In some patients associated hydrocephalus will
require shunting. Problems of the ear, nose, and throat are frequent
secondary to the facial abnormalities. Recurrent otitis media may
result in hearing loss, thus early hearing screening should be
performed. Maxillary hypoplasia leads to dental crowding and
malocclusion, which may require orthodontic treatment. Sleep apnea
treatment, if necessary, begins with adenotonsillectomy and may
progress to include more complex procedures.

The main orthopaedic problems include thoracolumbar
kyphosis, spinal stenosis, shortening of the extremities and angular
deformities of the knees. Kyphosis is noncongenital and it is centered
in the thoracolumbar junction. Treatment may be indicated to prevent
further development of the deformity and to assist in those that do not
correct with time (bracing); and in adulthood, to correct surgically
those cases in which kyphosis contribute to symptomatic spinal
stenosis. Spinal stenosis is the most serious problem and usually
develops in the third decade of life. Spinal decompression is indicated
as soon as the diagnosis is made. Limb lengthening remains
controversial but is gradually gaining greater acceptance. If the lower
extremities are lengthened, the humeri should be lengthened also to
facilitate personal care. Treatment of the genu varum usually requires
surgery because bracing is not effective. Fibular head epiphysiodesis,
fibular shortening, and tibial osteotomies can be performed to correct
the deformity usually not until age 4 at the earliest. Interestingly,
severe degenerative arthritis is not common in adults with
achondroplasia.

Vitamin D-resistant rickets, also know as familial hypophosphatemic rickets, encompasses a group of

disorders in which dietary intake of vitamin D is insufficient to
achieve normal mineralization of the growing bone. There are four types
of vitamin D-resistant rickets: phosphate diabetes (i.e., failure of
the reabsorptive mechanism for phosphate); failure of production of 1,
25-vitamin D (i.e., vitamin dependent rickets); end-organ insensitivity
to 1, 25 vitamin D, and renal tubular acidosis.

Historically, patients with these disorders were first
differentiated on the basis of their resistance to the ordinary
treatment doses of vitamin D and were found to have normal or near
normal levels of calcium, PTH, and vitamin D, but significantly
decreased serum phosphate and abnormal urinary excretion for phosphate,
water, amino acids, glucose, bicarbonate, ketone bodies, and glycine.

The condition usually becomes symptomatic between 1 and
2 years of age, and the disease is suspected because of the family
history, laboratory determination of phosphorus concentrations can lead
to the diagnosis in infants as young as 3 months. The usual presenting
complaints are delayed walking, short stature, and angular deformities
of the lower extremities (genu varum, although genu valgum may happen
in some cases). Systemic manifestation such as irritability and apathy
are minimal. The “rachitic rosary” may also occur. Spinal stenosis and
kyphosis has been described. Radiographically there is marked increase
in axial height and widening of the growth plates, cupping, and thin
and indistinct cortices and fuzzy, poorly defined trabecular bone
(osteopenia). Coxa vara may be present as well as lateral bowing of the
femur and tibia. Looser lines can be seen in the rib cage of a child
with florid rickets, resulting from accumulation of osteoid in the bone
matrix.

Medical treatment is best managed by a pediatric
nephrologist with expertise in metabolic bone disease. The usual
treatment consists of oral neutral phosphate replacement and the
administration of vitamin D, and the correction of the metabolic
abnormality present. The orthotic management to correct the lower
extremity deformities has proven ineffective. If patients experience
pain and increased deformities, surgical correction of the angular
deformities should be performed. Multilevel osteotomy is usually
required with intramedullary fixation or external fixation. Because of
a high risk of recurrences in the younger patient, surgery should not
be performed in early childhood.

Mucopolysaccharide excretion in the urine characterizes
this group of genetic disorders, and these disorders are among the
first skeletal dysplasias to be described and also among the first to
be understood at the biochemical level. There are at least 13 types (Table 9-1), and each type produces a particular

sugar in the urine because of a specific enzyme defect. The incidence is about 1 in 20,000 live births.

The intracellular degradation of sulfated
glycosaminoglycans (heparin sulfate, dermatan sulfate, keratan sulfate,
and chondroitin sulfate) by lysosomal enzymes is abnormal leading to
intracellular accumulation of these incompletely degraded compounds in
the lysosomes themselves. They are classified based on their enzyme
deficiency and the type of substance that accumulates. The most common
types are Morquio’s and Hurler’s syndromes.

The incomplete product progressively accumulates in the
tissues such as the brain, the viscera, and the joints. This
unremitting process leads to the clinical progression of the disorders.
The child is normal at birth, being biochemically detectable by 6 to 12
months of age, and clinically symptomatic by 2 years of age. All these
disorders lead to abnormally short stature. And in some cases, there is
severe mental retardation (Hurler’s, Hunter’s, and Sanfilippo’s). There
are also abnormalities of the skull (enlarged, with thick calvarium)
and facies (coarse, gargoyle), and deafness. In some cases there is
hepatosplenomegaly and cardiovascular abnormalities. Radiographically,
the clavicles are broad and the scapulae are short and stubby. The
vertebral bodies are ovoid and scoliosis and kyphosis are frequent (Figure 9-10). There is acetabular dysplasia, coxa valga, and the iliac wings are flared.

The clinical course is variable, but most patients die
in the first two decades of life if untreated. Treatment is evolving
and some of these disorders have been treated successfully with bone
marrow transplantation. The preferred donor is an HLA-identical
sibling. Following successful transplantation, accumulation of the
mucopolysaccharide stops, and there is improvement in the coarse
facies, hepatosplenomegaly, and partially in the hearing. Research is
currently under way in the field of gene therapy for some of these
syndromes.

Orthopaedic treatment is directed to correct the
functionally impairing musculoskeletal deformities. Hip flexion
contractures and dysplasia often require surgical reconstruction,
including reduction, femoral and pelvis osteotomies. Cervical
instability may be present and C1-C2 fusion and halo immobilization may
be necessary. Kyphosis requires orthotic treatment or even surgical
spine fusion. Genu valgus may be treated with corrective osteotomies.

Hereditary multiple exostoses (HME), or diaphyseal
aclasia, is a highly penetrant, autosomal dominant trait characterized
by slightly stunted growth of long bones and multiple osteochondromas.
Osteochondromas are cartilage-capped excrescences of bone that develop
at the growth plate level during growth. These osteochondromas are
indistinguishable morphologically from the solitary cases. HME has an
incidence of about 1 in 50,000 live births. The median age at the time
of diagnosis in affected individuals is approximately 3 years. By the
second decade of life, nearly all affected individuals will have
exostoses as the penetrance of the disorder has been found to be 96 to
100%. Many patients with HME require resection of the lesions due to a
mass effect or neurovascular impingement symptoms. Importantly, up to
3% of patients with HME will eventually develop a malignant
chondrosarcoma.

Over the last decade, advances in molecular biology and
genetics have permitted a better understanding into the molecular
players underlying these lesions. Linkage analysis has located three
etiological genes for HME, EXT1, EXT2, and EXT3. Interestingly,
mutations in any of these genes demonstrate very similar clinical
manifestations. These EXT loci have defined a new class of putative
tumor suppressor genes, to which have been recently added three related
genes, EXTL1, EXTL2, and EXTL3.

Because both HME and sporadic osteochondromas have been
associated with loss of heterozygosity at one or more of the EXT loci,
a neoplastic model of pathogenesis has been suggested. The Knudson
“two-hit” theory of carcinogenesis derived from familial retinoblastoma
has been applied to HME. Both copies of the EXT1 gene have been
observed to be deleted and gene losses and mutations have been observed
in chondrosarcomas arising from osteochondromas. However, it is still
unclear how EXT1 and EXT2 can function as tumor suppressors.

Patients present with several hard, knobby lumps near
the joints. Numerous sites can be involved, typically five or six
exostoses can be found in the upper and lower extremities. The most
common locations are distal femur (70%), proximal tibia (70%), humerus
(50%), and proximal fibula (30%). Over time, the extremities will
shorten in relation to the trunk, and legs will grow unequally. As the
lesions enlarge, they may cause discomfort secondary to mechanical
pressure to adjacent soft tissues and muscles. They rarely cause
neurological dysfunction. Often, patients complain of an undesirable
cosmetic appearance. Valgus deformity of the knee and ankle are not
uncommon, and osteochondromas of the proximal femur may lead to
dysplasia of the hip, which may require corrective osteotomies. In
adults, sarcomatous transformation will present as a painful and
enlarging mass in an area of previous deformity.

Treatment for multiple hereditary exostoses is surgical
excision. However, not all the exostoses should be removed. Established
indications for surgery include growth disturbances leading to angular
deformities or hip dysplasia; functional limitation of joint range of
motion; spinal cord compression with neurological compromise; painful
mass and obvious cosmetic deformity, and rapid increase in the size of
the lesion. Deformities in the forearm should be treated early to
prevent further progression and to reduce disability. Knee osteotomies
are associated with a high incidence of peroneal nerve palsy.