Localized Disorders of Bone and Soft Tissue

Although in most cases the disorder is evident from the
time of birth or infancy, a few cases have been reported in which
features appeared as late as 6 years of age. There is no recognized
pattern of inheritance. The lower extremities are affected at least ten
times more often

than the upper extremities. The affected limb is longer than normal in 90% of the patients (16,37,46). Usually, all bones and soft tissues in the limb are involved in the hypertrophy (Fig. 10.2).

The growth patterns of the affected limbs have not been
rigorously studied over time, but there are enough reported cases of
nonuniform overgrowth to caution the physician that prediction of an
eventual discrepancy should be done only as a rough estimate.
McCullough and Kenwright described two patients in whom the discrepancy
decreased with growth (47). Severe leg-length discrepancy is uncommon. In one study only 10% of the children had a discrepancy greater than 3 cm (37).
In addition to the hypertrophy of the extremity, there is evidence of
fundamental embryologic regulatory defects, especially distally, with
25% of patients having anomalies of fingers or toes, such as
macrodactyly, syndactyly, polydactyly, and clinodactyly (46). Carpal tunnel syndrome has been reported in children (48).
Scoliosis affects at least 5% of patients, although it rarely requires
surgery. An adult with a right thoracic scoliosis and hypertrophy of
the seventh thoracic vertebra presented with severe spinal stenosis (49).
An arteriovenous fistula, medullary angioma, and extradural venous
vascular malformation contributed to the stenosis, which was treated
successfully by decompression (49). Systemic
involvement may occur. In the central nervous system, AVMs and cerebral
and cerebellar hypertrophy have been described (50,51).
The gastrointestinal and genitourinary system may be involved,
resulting in bleeding in some cases. Surface bleeding from the
hemangioma occurs in 25% of patients, and 15% have clinical pulmonary
emboli, spontaneously or after operation (33).
Congestive heart failure may occur in patients with large vascular
malformations. Despite these complications, the life expectancy is not
markedly decreased. The impact of this complex medical condition on the
child’s psychosocial development should not be underestimated.

Most notably, venous fibromuscular dysplasia, consisting
of hypertrophied, irregular, or absent medial layers of the veins,
allows dilatation. Valves are anomalous; they are absent or obstructed.
Deep venous channels are usually present, and AVMs are uncommon (40). Lymphatic hypoplasia is common. Other tissues, such as nerve and subcutaneous tissue, may be hypertrophied.

Neurofibromatosis may produce massive hypertrophy
without prominent nevi. Maffucci syndrome often includes limb-length
inequality with vascular malformations, but it is differentiated by the
presence of intraosseous enchondromas. Beckwith-Wiedemann syndrome
involves localized overgrowth but also includes neonatal hypoglycemia,
visceromegaly, macroglossia, and a predisposition for Wilms tumor.
Proteus syndrome is a more severe disorder that includes virtually all
the features of Klippel-Trenaunay, and also soft-tissue tumors,
pigmented skin lesions, and thickened palms and soles (34). Bannayan-Zonana syndrome is characterized by thoracic and abdominal lipomatosis, vascular malformations, and macrocephaly (52).

Plain radiographs, limb-length evaluation, color duplex
ultrasonography, MRI, MR angiography, MR lymphangiography, and
lymphoscintigraphy can provide sufficient information for diagnosis and
planning in most cases (28,37,52,53,54). Lymphatic imaging is particularly useful in the evaluation of children with massive hypertrophy (37).
When the surgeon is planning for hemipelvectomy or hip disarticulation,
arteriography may be helpful to map major vessels to anticipate
significant bleeding (16). Contrast angiography is also useful for percutaneous treatment of a vascular malformation.

The skeletal and vascular abnormalities of
Klippel-Trenaunay syndrome are usually not dramatically progressive.
Surgery has a limited role in this condition. It should be done only
for disabling problems and when the benefit is fairly predictable (54).
Initial therapy of the aching, hypertrophic limb with varicosities
should consist of compression. Intermittent pneumatic compression
should be applied at night, using a custom-fitted garment and a home
pump, inflated every 90 seconds to a pressure midway between diastolic
and systolic (55). Just before getting up in
the morning, a Jobst compression garment should be applied, and worn
throughout the day. With these measures, a marked decrease in limb
girth, resolution of cardiac overload and dependent syncope, reduced
discomfort, and marked improvement in function can be seen. A technique
of manual lymphatic drainage can also be used, if there is a
significant lymphatic component to the malformation (31).
Thrombophlebitis and pulmonary embolism are common. Consultation with a
vascular surgeon may be beneficial for most of these patients.

Surgery is beneficial in selected situations. These
include: cardiac failure from shunting in children; overgrowth that is
nonresponsive to compression therapy; rapid enlargement in limb size;
bleeding from abnormal vessels in the gut, kidney, or genitalia;
coagulopathy; reconstruction in selected cases of syndactyly or
polydactyly; and amputation of severely disfiguring dysfunctional limbs
for which reconstruction is not an option and where amputation may
provide a more functional limb. The site of amputation is often
dictated by the extent and severity of the vascular malformation. A
knee disarticulation is preferred to a midthigh amputation because it
is an end-bearing stump with rotational control and better suspension;
the distal femoral physis is preserved, and overgrowth is avoided.
Midthigh amputation requires ischial weight bearing, which may be a
problem in the presence of any scarring or gluteal vascular
malformations (34,56,57).
Risks of surgery include infection, particularly in children with
abnormal lymphatic drainage, and delayed wound healing, which is

common after transverse amputations (58).
Occasionally, a proximal limb disarticulation is needed in neonates as
a life-saving procedure. For patients in this age group, hypothermia
and total circulatory arrest for up to 60 minutes have been successful
as an adjunct for minimizing blood loss (59). Pulsed-dye laser treatments can be used for treating the cutaneous vascular malformations over limited areas (37).

Certain procedures have low success rates. Surgery to
debulk the extremities has usually resulted in recurrence or minimal
improvement. Varicose vein ligation may provide relief to local
symptoms, but the varicosities often recur, and ligation should be
avoided if the deep venous system is not patent. Epiphysiodesis is used
in the treatment of leg-length discrepancy, but the growth patterns are
unpredictable. The procedure does not decrease the widths of the
affected extremities. Limb shortening at skeletal maturity may be the
most accurate technique. If surgery is planned, the skin involved
should be protected, and the increased risk of deep thrombosis has to
be borne in mind.

The etiology of Proteus syndrome remains unknown.
However, it has been suggested that Proteus syndrome and other similar
sporadic congenital hamartomatous syndromes such as
encephalocraniocutaneous lipomatosis and epidermal nevus syndrome
represent a phenotypic continuum that arises through somatic mosaicism.
The concept of lethal autosomal (somatic) mutations that can survive
only in a mosaic state is supported by sporadic occurrence,
distribution of lesions in a scattered or asymmetric pattern, variable
extent of involvement, and equal sex ratio (65,66). Germline loss-of-function mutations in PTEN,
a tumor suppressor gene on 10q23.3 that encodes a dual-specificity
phosphatase involved in various cell-survival pathways, have been noted
in up to 20% of patients with Proteus syndrome and 50% of patients with
Proteus-like syndrome. The PTEN syndrome spectrum includes other
disorders that are characterized by hamartomata, lipomatosis, and
neoplasia (67,68,69).

The cutaneous vascular malformations of Proteus syndrome
include capillary, lymphatic, capillary-venous and
capillary-lymphatic-venous types, with an overall predominance of
lymphatic vessels (70). Subcutaneous tumors,
found most commonly on the trunk, are composed of adipose and fibrous
tissue, Schwann cell structures and vascular tissue. Extraskeletal
manifestations of the disorder can include hemimegalencephaly,
opthalmologic anomalies, and splenic hyperplasia (71,72,73). Unusual neoplasms have been described, and precocious puberty may result from juvenile granulosa cell tumors (74,75).
Severe cystic emphysematous pulmonary disease and sudden death by
pulmonary thromboembolism can occur, even in young children (76,77).
MRI is helpful in delineating the nature and extent of the subcutaneous
tumors as well as in aiding in the diagnosis of the syndrome (60,71,78).

Macrodactyly is a common manifestation and can occur both in the hands and in the feet (60).
The enlarged digits may not be located on the same side as the
hemihypertrophy. The macrodactyly progresses rapidly in the first few
years of life, and slows in later childhood and adolescence. Severe
cosmetic and functional problems can result. The histology is a
hamartomatous proliferation of all mesenchymal tissues, especially the
osseous and fibrofatty components (63).
Treatment will be discussed in the section on macrodactyly later in
this chapter. A striking finding in the foot is plantar hypertrophy,
resulting in cerebriform or gyriform creasing (Fig. 10.3).

Hemihypertrophy may be partial, complete, or crossed,
and it results in limb-length discrepancy which varies greatly.
Overgrowth and progressive atrophy have been described (61).
Angular upper- and lower-limb deformities are seen in Proteus syndrome.
Genu valgum occurs commonly, recurs after bracing, and often requires
repeated osteotomies (61,63) (Fig. 10.4). Joint contractures and angular deformities may be caused by epiphyseal exostoses (61).

Scoliosis or kyphoscoliosis occurs in approximately 50% of children with Proteus syndrome and may require fusion (60,61,62,63,64). The effect of bracing is not known. Spondylomegaly, or localized spinal overgrowth, has been

reported. It can result in progressive spinal deformity and compressive neuropathy from canal stenosis (63,79,80,81). Infiltration of the spinal canal by an angiolipomatous mass can also occur, and may lead to paraplegia (79,80,82).

Treatment is directed mainly at correction of
limb-length inequality, angular deformity, and hypertrophy. Because the
skeletal age may be delayed and the rate of progression of limb-length
inequality is not well understood, planning the treatment can be
difficult. Extensive overgrowth and joint contractures may lead to
amputation. During extensive surgical excisions, residual abnormal
tissue is often needed in the reconstruction, and postoperative lymph
drainage may be prolonged (83). Patients who
are scheduled for surgery should have a thorough assessment of their
airway and pulmonary functions because of the relatively high frequency
of pulmonary involvement and tonsillar hyperplasia (84).
Close monitoring and treatment of deep venous thrombosis is important
because of the increasingly recognized risk of fatal pulmonary embolism
(76).

Osteolysis is initially localized to one bone and may
subsequently involve adjacent bones. The joints and intervertebral
discs do not act as barriers to extension. Typically, progressive bone
resorption occurs, and the bone is replaced by fibrous tissue. The
resorption may stop spontaneously on rare occasions. The peak age at
onset is in the second and third decades of life (86).
Gorham disease is differentiated from other forms of idiopathic
osteolysis on the basis of its lack of association with neuropathy or a
genetic mode of transmission (87). It may involve any area of the skeleton but is most common in the shoulder, pelvic girdles, and spine (86,88,89,90).
It may present as a dull ache and weakness in the segments involved,
and is associated with increasing deformity and pathologic fractures.
Patients with lesions extending outside the bone have a high mortality
rate, approaching 50%, from chylothorax, chylopericardium,
chyloperitoneum, and cachexia (23,88,91,92,93) (Fig. 10.5A).

Plain radiographs show single or multiple intramedullary and subcortical radiolucent foci, which eventually coalesce (94).
There is subsequent disappearance of contiguous bones and tapering of
the bony remnants. No sclerosis or osteoblastic reaction is seen. If a
pathologic fracture occurs, and if the lysis is minimal, the bony
lesion may be overlooked initially. Unlike in normal fracture healing,
the bone ends eventually become tapered, and there is no evidence of
the formation of new callus. CT scan is the best method for evaluating
the extent of bone destruction. Arteriography, venography, and
lymphangiography do not reveal the intraosseous lesions (89).
Nuclear medicine scans are inconsistent in showing the lesions. MRI is
very helpful, but the signal characteristics vary depending on the
stage of the disease process (87,88,95).
The neovascular tissue is bright on T1 and T2 imaging early, but the
predominant fibrous tissue that is present late in the process is dark
on T1 and T2 imaging (Fig. 10.5B. The
differential diagnosis includes other rare causes of idiopathic
osteolysis, including syndromes that have generalized osteolysis as a
clinical feature, such as Winchester syndrome (96).
Other conditions with more focal osteolysis exist, such as idiopathic
multicentric (carpotarsal) osteolysis, which is characterized by
nephropathy and osteolysis predominantly involving the hands and feet (97,98), and

Hadju-Cheyney syndrome, in which acroosteolysis predominates (99).

Histologic studies demonstrate numerous thin-walled
vessels, lined by endothelial cells. The vessels may be empty or may
contain proteinaceous fluid and/or blood cellular elements (91).
Fibrous connective tissue replaces the bone. There is no evidence of
malignancy or inflammation. The histologic changes are similar to
benign hemangioma or venous malformation of bone, but there is much
more extensive bone destruction (86). The cause is unclear, but perivascular cells of the lesion show the characteristics of osteoclast precursors (89). The bone shows enhanced osteoclast activity that appears to be caused by an increase in the sensitivity
of osteoclast precursors to humoral factors that promote osteoclast
formation and bone resorption, rather than to an increase in the number of circulating osteoclast precursors (100,101).

No treatment has been shown to be consistently
successful, but surgery, with or without radiation therapy, has been
the mainstay of treatment. Some cases, especially those without
significant involvement of chest or abdominal cavities, stabilize
spontaneously, although return of the “vanished” bone does not occur.
This complicates the evaluation of published treatment protocols. Local
resection and bone grafting, with or without internal fixation, have
not been consistently successful (86). Most
grafts are resorbed, but there is one report of the successful use of a
vascularized fibular graft in pelvic-femoral reconstruction (102). Wide resection and limb salvage, with or without prosthetic reconstruction, can be successful (86,87,103). Amputation has been required in order to achieve a satisfactory margin and improved function in some patients (86,102). Radiation has been shown to be an effective adjunct therapy, when doses of 30 Gy or more are used (86,104,105).
The management of vertebral and rib involvement with chylothorax is
difficult. Resection with adequate margins is usually not possible.
Surgical decompression with anterior and posterior fusion and
instrumentation can successfully manage neural compression and
instability at the cervicothoracic junction (106). Radiotherapy, combined with pleurodesis and pleural adhesion therapies, has proved promising in some cases (88).

Most cases of macrodactyly are evident soon after birth,
although occasionally the dynamic type may not become apparent until
later in infancy, when relentless enlargement occurs (Fig. 10.7).
The upper extremities are more commonly affected than the lower
extremities. Unilateral involvement occurs in 95% of cases, but in
two-thirds of the patients, more than one digit on the affected side,
usually adjacent ones, are affected (130). The
second ray is the most commonly enlarged, followed in descending
frequency by the third, first, fourth, and (very rarely) fifth rays.
Syndactyly may coexist. Usually, the palmar or plantar surface is more
hypertrophied than the dorsal, resulting in hyperextension of the
metatarsal or metacarpophalangeal joints (134,135).
If two adjacent digits are affected, they grow apart from each other.
In static macrodactyly, the digits involved are approximately 1½ the
normal length and width. In the dynamic type, even more striking
enlargement may occur. The bone age may be advanced in the phalanges
involved (134,136). The metacarpals or metatarsals may be enlarged, thereby widening the hand or foot (134). The width of the forearm, leg, thigh, or arm on the affected side may also be subtly increased (136).
Not long after skeletal maturity, interphalangeal joint stiffness and
degenerative changes may supervene prematurely, even in untreated cases
(130).

The pathology varies, depending on the etiology of the
macrodactyly. The most consistent feature is overgrowth of the
fibro-fatty tissue, but all tissues are enlarged in the digit involved (130,134,136).
Fibrous bands and hypertrophied adipose tissue infiltrate muscle and
nerve. A proliferation of fibroblastic tissue between the cortex and
periosteum may account for the phalangeal overgrowth (134,136).
The digital nerves are more prominent than usual, particularly in the
hand, with proliferation of epineural and perineural tissue (130,131,134). Plexiform neurofibromas are typical in neurofibromatosis (131).
In children who have met strict criteria for the diagnosis of Proteus
syndrome, macrodactyly is not associated with enlarged digital nerves
or fibroadipose tissue proliferation (133).

The pathogenesis of macrodactyly is unknown, but neuroinduction is considered a possibility (131,134).
Occult neurofibromatosis was once thought to be the cause, but
long-term follow-up studies, including one of 26 years, have failed to
reveal the development of features of neurofibromatosis other than the
macrodactyly itself (137).

The operative treatment varies, depending on the
location, type, and severity of the macrodactyly. The management
considerations for the hand are very different from those for the foot.
In the hand, function is paramount, and a significant increase in the
width and length of a digit can be tolerated, whereas, in the foot,
accommodating even a small excess of width in a shoe may be difficult.
A good cosmetic result can be difficult to achieve. In the static type
of macrodactyly, debulking and shortening procedures such as phalangeal
resection and epiphysiodesis are successful. In contrast, the deformity
seen in progressive forms will usually require ray resection. Extensive
debulking can interfere with the blood supply to the skin and result in
delayed wound healing.

Mild-to-moderate macrodactyly can be managed by a
two-stage (3 months apart) soft tissue debulking procedure, provided
length is not a problem (130). If length is a
problem, then epiphysiodesis of the proximal phalanx, and of the
metacarpal or metatarsal, if involved, will be effective in the young
child (<6 to 8 years) (130,134,138,139). In the older child, bone shortening by phalangeal resection can be combined with staged debulking (140,141).
Ligament reconstruction or fusion with Kirschner wire fixation will
avoid the reported complications of floppy toes or secondary
deformities (137). Isolated phalangeal amputation should be avoided because of subsequent angular deformities of the adjacent toes (132,137).

Digital shortening and debulking have not been
effective, in the long term, for dealing with excessive forefoot
widening. Ray resection is a more definitive solution to the multiple
dimensions of enlargement that are often encountered (131,137,142,143).
One or two rays may be removed, but the first ray of the foot should
not be amputated in isolation because of its unique function in balance
and weightbearing (144). Ray resection results in good cosmetic and functional outcomes in feet with less toe involvement (144).
In order to improve correction and avoid recurrence, it has been
suggested that a wedge of adjacent tarsal bones be resected when doing
a ray resection (131). Ray resection prevents
crossover of the adjacent digits and eliminates “gap” formation and
soft-tissue enlargement. Three rays are the minimum requirement for a
foot to be functionally serviceable. More extensive involvement of the
foot would necessitate midfoot or Syme disarticulation, depending on
the extent of overgrowth.

As the patient matures, a subtle increase in width may
be seen in all levels of the limb. Herring and Tolo reported a case of
macrodactyly with width increase in the absence of any overall
limb-length discrepancy (145). The family
should be counseled from the first visit that this condition is complex
and involves multiple tissues and levels. They need to know that
multiple procedures may be necessary

and
that early, appropriate, aggressive resections, involving all affected
dimensions, may decrease the total number of surgeries required. For
example, as soon as it becomes apparent that length and width may be
excessive, resection of one or several rays, with shortening or
epiphysiodesis of an adjacent ray, may be appropriate. Often, several
consultations with one or more surgeons may be necessary to help
families come to this realization.

The clinical presentation of congenital constriction
band syndrome is quite variable. The bands may be superficial and
incomplete or extend deeply to the underlying bone and may be
circumferential. Multiple bands may be present in a single extremity.
Swelling often results from impaired venous and lymphatic drainage
distal to the site of constriction. In the case of deep,
circumferential bands, there may be significant neurovascular
impairment (147,148,149,150,151,152). With growth, the constriction band occasionally gets more severe and may become increasingly symptomatic (147).
Upper extremity involvement is more frequent than lower extremity
involvement. Head, neck, or trunk constriction bands can occur but are
very uncommon (153). The distal aspect of the
limb, particularly the longest digits (index, long, and ring fingers,
and great, second, and third toes) are most frequently affected (146,147,148,154). Craniofacial abnormalities, including cleft lip and palate, are seen in 7% of children with constriction band syndrome (147,150,155).

Patterson developed a classification system on the basis
of the severity of the syndrome: simple constriction rings;
constriction rings associated with deformity of the distal part, with
or without lymphedema; and constriction rings associated with
syndactyly and intrauterine amputation (156).

Amputations and syndactyly are seen in more than
one-half of the children who are affected. Transverse, terminal, and
digital amputations with normal proximal skeletal development are
typical (146,147,148,154) (Fig. 10.8A). Simple syndactyly is common, whereas complex syndactyly with bony fusions is rare (148).
Acrosyndactyly or fenestrated syndactyly, in which there is an open
cleft between digits joined distally, may also occur. Hypoplastic or
absent nails are a consistent feature of the condition (147).

The incidence of clubfoot in constriction band syndrome ranges from 12% to 56% (146,147,148,150,151,156) (Fig. 10.8B).
These feet are often rigid and more difficult to treat than idiopathic
clubfoot. Approximately 30% to 50% of the clubfeet are classified as
paralytic (149,150,152,157).
These feet show weakness of the peroneal muscles and are typically
associated with deep ipsilateral constriction bands in the lower leg.
The bands in the paralytic form of clubfoot are thought to cause a
compression neuropathy, direct muscle injury, or compartment syndrome.
Nonparalytic clubfeet associated with the disorder may or may not have
ipsilateral constriction bands; these bands are typically superficial
or incomplete and are considered to be idiopathic or resulting from
oligohydramnios (148).

Angular deformity, bone dysplasia, and pseudarthrosis
can occur below the constriction bands in the upper and lower
extremities (156,158,159).
Anterolateral tibial bowing appears similar to that seen in congenital
pseudarthrosis of the tibia associated with neurofibromatosis; but, in
contrast to the latter situation, remodeling can occur and realignment
osteotomies, if required, will heal (158) (Fig. 10.8C). Rapid, spontaneous healing of osseous defects in the forearms and tibiae of infants has been described (158,159). Zionts et al. prefer the term discontinuity rather than pseudarthroses in describing these defects, because of the spontaneous healing (159).

Leg-length discrepancy exceeding 2.5 cm has been reported in up to 25% of the children who are affected (148).
Surgical management to equalize limb length will be required in some of
these children, depending on the predicted discrepancy at skeletal
maturity.

Despite many theories, the etiology and pathogenesis of
constriction band syndrome remain unclear. The two main conflicting
theories focus on whether the band formation is the result of factors
intrinsic or extrinsic to the embryo or fetus, but the disorder may be
more heterogeneous than had been thought.

The theories favoring extrinsic origin have the widest
acceptance. Torpin has proposed that entanglement of the limbs in
defects or free strands of amnion result in constriction band syndrome (160,161).
Supportive evidence includes the lack of hereditary factors, the
ultrasonographic demonstration of prenatal amniotic bands, the
involvement of the longer digits and the histologic demonstration of
amnion in constriction bands. Amniocentesis in animals produces fetal
malformations that resemble constriction band syndrome in humans. Kino
demonstrated in rats that the malformations result from subcutaneous
hemorrhages caused by excessive uterine contractions after
amniocentesis (146). A study that reviewed
children with clubfeet and constriction band syndrome showed that there
was a history of attempted first-trimester abortion in 60% of them (152).
Although an association between amniocentesis or fetal blood sampling
and the occurrence of amniotic band syndrome in humans has been
suggested (162), evidence for this remains inconclusive.

The theory of intrinsic etiology, proposed by Streeter,
suggests that a defect of the subcutaneous germ plasm causes
soft-tissue necrosis and subsequent healing, with the formation of
constriction bands (163). There is evidence that in utero
vascular disruption from the death of a co-twin, or from placentally
derived embolic infarcts, can cause constriction band syndrome (164).
In these children, there was no ultrasound evidence of amniotic bands.
It therefore appears that this syndrome may result from factors other
than amniotic entanglement.

The differential diagnosis is limited, but there are some interesting conditions to consider. The Michelin tire baby syndrome consists of multiple benign circumferential skin creases. This is an autosomal dominant condition that has

been traced through as many as four generations in one family. These
creases are present from birth, predominantly involve the extremities,
and disappear by 5 years of age (165). Hair/thread constriction may occur in infants, usually younger than 2 years of age, and cause circulatory compromise (166).
Strands of hair or fabric may become wrapped around fingers and toes
tightly enough to cause distal swelling and circumferential laceration
of the skin. It may be difficult, at the time, to see the hair or
thread that is causing the problem, thereby making it difficult to
distinguish the condition from a congenital constriction band. The
absence of a family history of constriction rings at birth should
suggest the diagnosis of hair constriction. Ainhum is a disorder
characterized by ulceration at the base of the fifth toe on the plantar
surface; it progresses to a circumferential constriction ring with
autoamputation. It is seen mainly in Africa (167).

Superficial, asymptomatic constriction bands do not require treatment. Excision of

the band and closure with multiple Z-plasties is indicated: (a) in
bands that extend to the deep subcutaneous tissue or fascia; (b) if
there is edema distal to the band; (c) if there is vascular
insufficiency or neurologic deficit; and (d) if the band is increasing
in severity. In some cases, emergent surgical release in neonates may
be indicated in order to salvage the limb (Fig. 10.9). The surgical release used to be done in stages, releasing one-half of the band at a time with a 6- to 12-week interval (148,156,168).
This was because of concern that impaired venous or lymphatic flow and
skin-flap necrosis might occur if the whole band were released in one
stage, but single-stage release of constriction bands can now be done
safely (168).

Clubfoot in neonates with an ipsilateral constriction
band can be treated with serial manipulation and casting only if there
is no significant foot edema or evidence of neurovascular compromise.
Nonoperative management is rarely successful in these children,
especially when the clubfoot is of the paralytic variety (151,152,157).
The severity of the clubfoot appears to be more important than the
presence or severity of the constriction band in predicting the outcome
of surgical treatment (152,157). Paralytic clubfeet with deep bands often require multiple procedures and usually have poorer outcomes (169).
Resection of the constriction band should be done prior to surgical
release of the clubfoot in order to avoid neurovascular compromise.
Muscle imbalance of the foot, resulting from peroneal weakness, can be
managed by a split transfer of the tibialis anterior tendon (150,157).

Surgical intervention in children with acrosyndactyly is
generally done between the ages of 6 months and 1 year because of the
severity of the deformity and in order to allow for longitudinal growth
and function of the affected digits (154).

In utero surgical lysis of constriction bands has been reported (170), but this must be balanced against reports of spontaneous resolution of bands noted on serial ultrasonographic evaluation (171).

We perform single-stage, circumferential surgical
release of deep, symptomatic constriction bands. The constriction band
and underlying fibrous tissue extending through the skin, subcutaneous
tissue, fascia, and muscle should be completely

excised
with an adjacent 1- to 2-mm cuff of normal tissue. To avoid injury to
compressed neurovascular structures, the nerves and vessels should be
exposed proximally and distally and followed under the constriction.
Skin closure utilizing multiple Z-plasties fashioned with large
60-degree flaps helps to avoid postoperative circumferential scar
retraction. Subcutaneous fat advancement flaps (SFAFs) can also be
utilized to achieve a more normal contour to the extremity (172).
In children with ischemia of the distal limb, a fasciotomy may be
required. Surgical treatment of the constriction band is generally
performed prior to any surgical treatment of foot deformities in order
to avoid swelling and neurovascular compromise. However, while excising
a deep band in the distal aspect of a lower leg that is associated with
a clubfoot, Achilles tendon lengthening and posterior capsular release
of the tibiotalar and subtalar joints can be performed through the
incision used for band resection. If necessary, more extensive
procedures on the foot should be delayed until healing has occurred
after the excision of the constriction band, and there is resolution of
the distal edema.

The exact cause of this autosomal dominant disorder and
the variability of its expression have not yet been fully elucidated,
but it appears to be associated with various missense mutations in the
gene encoding human transforming growth factor-β1 (TGFB1) on chromosome 19q13 (175,176,177).
The TGF-β family represents a class of signaling molecules that plays a
central role in morphogenesis, growth, and cell differentiation. TGFB1,
which is abundant in skeletal tissue and is stored in the bone matrix,
appears to act as a coupling factor between bone formation and
resorption. TGFB1 is secreted as a latent precursor, which consists of
a mature peptide and a latency-associated peptide (β1-LAP). TGFB1 can
exert its multiple functions only after going from this latent
precursor state to an active state in which the binding site of the
mature peptide for its receptor is no longer shielded by the
latency-associated peptide. It appears that the most common mutation in
the disorder involves an arginine-cysteine amino acid change at codon
218 (R218C) in the latency-associated peptide domain of TGFB1, which may lead to an increase in TGFB1 bioactivity (178,179,180,181).

Camurati-Engelmann disease is rare (1 in 1 million),
with boys being affected more often than girls (approximately in the
ratio 3:2) (182). The age at the onset of
symptoms is highly variable, with most individuals presenting in the
first decade of life. In one study, the mean age at onset was 15 years
and 4 months, with the ages ranging from 1 year to 70 years (182).
The clinical and radiologic manifestations are also variable. The most
common symptoms are limb pain, proneness to fatigue, headache, poor
appetite, and difficulty in running. Clinical signs include muscle
weakness and atrophy, thickening of the long bones, genu valgum,
waddling gait, and exophthalmus (182). If radiographs are not performed, these children can be mistakenly diagnosed as having neuromuscular disorders (183). Basilar skull sclerosis can lead to narrowing of cranial foramina with symptomatic auditory and optic nerve compression (184).
Progression usually occurs in a slow, unpredictable fashion but
occasionally will spontaneously stop. Patients have a normal life span.

Laboratory studies are not helpful in confirming the diagnosis. The alkaline phosphatase level is elevated in 40% of patients (185).
Biochemical markers of bone turnover may be useful for assessment of
disease activity, and may correlate with bone scan activity (186).

The plain radiographs demonstrate symmetric periosteal
and endosteal diaphyseal sclerosis, and diaphyseal widening. The tibia
is most frequently involved, but all the long bones in the upper and
lower extremities, and the clavicle, can be affected early in the
course of the disease. The cortex becomes wide and irregular with
narrowing of the medullary cavity (Fig. 10.10).
CT scans show that the thickening and sclerosis are irregular and
nonhomogeneous, and that endosteal involvement may be more extensive
than periosteal thickening (187). Sclerosis at
the base of the skull is common but is not an early finding. The
evolution, as evidenced by radiologic studies, is usually progressive,
with increasing sclerosis of the bone, extension to the metaphysis and
epiphysis, and eventual involvement of the metacarpals and metatarsals,
pelvis, and spine (182,185,188,189).
In the spine, only the posterior elements and the posterior aspect of
the vertebral body are affected, and there is no stenosis (187,189).
Technetium-99m bone scans demonstrate uptake in the middiaphysis of the
affected long bones early in the disease, often before changes show up
on the plain radiographs. MRI shows cortical involvement with sparing
of the medullary cavities but is not helpful in diagnosis or management
(189).

Other than the thickened cortex, there is no histologic
abnormality unique to progressive diaphyseal dysplasia. Early changes
are typical of recent bone formation, with woven bone and lack of
haversian system development, but modeling occurs later (184). Marrow fibrosis and narrowing of the medullary canal can occur, and this may explain the occasional patient with anemia (188).

Other sclerosing bone dysplasias associated with normal stature should be considered.

Considerable overlap exists in the classification of sclerosing bone dysplasias (190).
The diagnosis can be made by determining the inheritance pattern,
clinical and radiologic characteristics, and laboratory findings or
lack thereof. Ribbing disease has a similar radiologic appearance but
affects only the lower extremities and is not always symmetrical.
Extensive early cranial and facial involvement, an autosomal recessive
inheritance pattern, and mental retardation differentiate
craniodiaphysial dysplasia from progressive diaphyseal dysplasia.
Osteopetrosis is characterized by sclerosis throughout the skeleton,
with loss of the medullary canals. Infantile cortical hyperostosis, or
Caffey disease, is distinguished by neonatal onset, febrility,
hyperirritability, and soft-tissue swelling. Hyperphosphatasia may have
radiologic findings similar to progressive diaphyseal dysplasia, but
the alkaline phosphatase level is markedly increased. Hardcastle
syndrome is an autosomal dominant disorder with diaphyseal medullary
stenosis and sclerosis with pathologic fractures and malignant
transformation (191). Juvenile Paget disease,
infantile cortical hyperostosis, hypervitaminosis A, and fluorosis
should also be considered in the differential diagnosis.

There is no cure for this disorder and the treatment is
largely supportive. Nonsteroidal antiinflammatories may help decrease
limb pain, and physical therapy can be instituted to help maximize
function. Corticosteroid administration has been shown to reduce pain
in children as well as in adults, with inconsistent reports of
decreased diaphyseal uptake on Tc-99m bone scintigraphy (192,193,194,195).

Successful surgical realignment of the lower extremities of affected patients has been described by Clawson and Loop (188).
Knee flexion deformities, genu valgum, and external tibial torsion were
corrected by distal femoral and proximal tibial and fibular
osteotomies. The bone

was described as being soft and vascular but it healed uneventfully.

This nonhereditary disorder affects both sexes equally.
The typical presentation is with painless, asymmetric joint
contractures prior to 6 years of age (197,198).
The lower extremities are more frequently involved than are the upper
extremities. The underlying hyperostosis develops slowly and progresses
with age, usually more rapidly in childhood. The overlying soft tissues
may be thickened with lymphedema, and the skin is often tense, shiny,
erythematous, and sclerodermatous over the involved areas (199,200,201,202).
There is associated muscle atrophy and periarticular fibrosis with
contractures. Flexion contractures at the knee, hip, ankle and fingers,
and patellar dislocation are the most common joint deformities (198). Paraarticular ossification and synovitis can further impair joint motion (203,204).
Limb-length discrepancy and angular deformities around the knee and
ankle can result from fibrosis and physeal abnormalities. A mean of 4
cm of limb shortening was noted in one study of 11 children, although
one patient had overgrowth of the affected limb (198).
Melorheostosis does not shorten life span, but morbidity may be
considerable. Kidney anomalies, including minimal-change nephrotic
syndrome and renovascular hypertension secondary to renal artery
stenosis, have been described (205,206,207).

The etiology of this noninherited disorder is unknown.
It has been observed that distribution of the lesions correspond to
sclerotomes (204). One hypothesis is that an
infection analogous to herpes zoster occurs, and lesions spread along
the affected nerve roots with resultant scarring and osseous changes.
The sporadic occurrence of melorheostosis and osteopoikilosis, the
so-called mixed sclerosing bone dysplasia, in families with familial osteopoikilosis (an autosomal dominant disorder) has been reported (190,208,209),
and raises the possibility that the two disorders may be related. Kim
et al. suggested that the altered expression of several adhesion
proteins may contribute to the development of the hyperostosis and
associated soft-tissue abnormalities in melorheostosis, in view of the
downregulation of human transforming growth factor-β-induced gene
product (betaig-h3) in skin fibroblasts from affected regions (210).

The classic radiographic appearance of melorheostosis is
asymmetrical bands of sclerosis in an irregular, linear pattern often
described as molten wax flowing down the side of a candle (Fig. 10.11). In children the hyperostosis is endosteal, whereas in adults it is in an extracortical, subperiosteal location (202,203).
The hyperostosis can be located throughout the skeleton, typically on
one side of the diaphysis of long bones, the pelvis, and in the hands
and feet. The ribs, skull, and spine are affected least often. Patches
of hyperostosis, rather than a linear pattern, are present in the
carpal and tarsal bones and the epiphyses. This is similar to what is
seen in osteopoikilosis. Bone scans reveal increased uptake in the
areas involved.

The hyperostosis consists of woven or nonlamellar dense bone with thickened, sclerotic, and irregular laminae (203). An abundance of osteoid without mineralization suggests the overproduction of bone matrix in affected bone (211).
Increased expression of procollagen α1(I) mRNA and secretion of
α1(I),α2(I) andα1(III) collagen has been noted in skin biopsies
overlying the bone involved (212).

The differential diagnosis includes osteomyelitis,
osteopetrosis, osteopoikilosis, and osteopathia striata, all of which
can have similar radiographic findings. Mixed sclerosing bone dysplasia
comprises melorheostosis and osteopoikilosis and/or osteopathia striata
in the same individual (190,208,209).
The transient periosteal reaction in infantile cortical hyperostosis is
less dense and is found in different locations. Focal scleroderma may
cause soft-tissue fibrosis and contractures, but the bones are
radiologically normal (213).

The soft-tissue contractures are resistant to manipulation, bracing, and serial casting (214).
Non-steroidal antiinflammatory medications can ease discomfort.
Surgical treatment including soft-tissue releases, capsulotomies, and
osteotomies are difficult to carry out, and incomplete correction or
rapid recurrences of the deformity are common, sometimes necessitating
an amputation (198,203).
Distal limb ischemia can occur when the chronically contracted and
flexed joint is extended. Osteotomies that permit shortening may avoid
this complication.

The Ilizarov technique has been used in a small number
of children for lengthening, realignment of angular deformities, and
correction of joint contractures (214,215,216,217,218).
Realignment and lengthening have been done successfully, but
complications include pseudarthrosis and, in one child, ischemia that
caused pain and led to loss of function and eventual amputation of the
affected part (215,217).

This disorder develops during childhood and persists
throughout life. The children have normal stature and most are
asymptomatic, but up to 20% may have mild articular discomfort
associated with joint effusions (219). The
diagnosis is often made as an incidental radiologic finding. Fractures
heal uneventfully and pathologic fractures have not been reported. The
risk of malignancy is probably not higher than in the normal
population. Osteopoikilosis is frequently seen in association with
another hereditary dermatologic condition, dermatofibrosis lenticularis
disseminata, or Buschke-Ollendorf syndrome, which is marked by the
presence of papular fibromas (220,221).
This syndrome is usually asymptomatic, but soft tissue fibrosis and
joint contractures that appear clinically similar to those seen in
melorheostosis can occur. Osteopoikilosis has also been described in
association with melorheostosis, the so-called mixed sclerosing bone
dysplasia (190,208,209).

The osteosclerotic nodules are well-defined,
homogeneous, bilateral, circular- to ovoid-shaped from 1 to 15 mm in
width, and are located in the metaphyses and epiphyses of long bones,
the carpus, the tarsus, the pelvis, and the scapulae (Fig. 10.12). The ribs, clavicle, and skull, are not involved (219,222). The lesions may increase or decrease in size or number (222).

Bone scan usually does not demonstrate increased uptake in the lesions (223).
This is useful in differentiating this condition from metastatic
carcinoma of breast or prostate that may have a similar radiographic
appearance. Mastocytosis should also be considered in the differential
diagnosis.

The etiology and pathogenesis of osteopoikilosis are not
clear. The sclerotomal distribution and association with abnormalities
of mesodermal tissues suggests a relation between this condition and
other osteosclerotic disorders (220,222,224).
The concept of mosaicism, due to nondisjunction or anaphase lagging
resulting in an individual with two or more cell lines with different
karyotypes, may explain the occurrence of osteopoikilosis, an autosomal
dominant disorder, occurring along with melorheostosis, a sporadic
disorder, in so-called mixed sclerosing bone dysplasia. The
melorheostotic component may be caused by early loss of the
corresponding wild-type allele at the gene locus that gives rise to
isolated familial osteopoikilosis (190,208,209,225).

The sclerotic areas consist of focal condensations of compact lamellar bone within the spongiosa (219,224).

There is no treatment for this benign disorder. In the
rare cases of associated fibrosis and joint contracture, the management
is the same as for melorheostosis.

This is a rare, autosomal dominant disorder that
exhibits no physical or laboratory abnormalities. The diagnosis is
usually made on an incidental radiograph.

The radiographic hallmark is dense linear striations in
the tubular and flat bones with the exception of the skull and
clavicles. These lesions do not change with time. In the long bones,
the striations are parallel to the long axis and affect mainly the
metaphyses, but may extend into the epiphyses also (Fig. 10.13).
A fan-shaped pattern of linear striations can be seen in the iliac
wings, likely reflecting the growth pattern of the pelvis (227). There is no increased uptake on bone scan.

Osteopathia striata occurs occasionally as an osseous
constituent of a more complex sclerosing bone dysplasia, such as mixed
sclerosing bone dysplasia, where it may be found in association with
osteopoikilosis and/or melorheostosis (224,227,228).
Osteopathia striata with cranial sclerosis (OS-CS) is a rare syndrome
characterized by longitudinal striations of the long bones and
sclerosis of the craniofacial bones in association with typical facies,
macrocephaly, conductive hearing loss, mental retardation, and other
manifestations (229,230). Severe cervical kyphosis has been noted in one patient with this disorder (231).
Sponastrime dysplasia includes osteopathia striatalike radiographic
findings, characteristic facies, and vertebral anomalies (232,233). Symptomatic osteopathia striata is also a characteristic of X-linked focal dermal hypoplasia (234).

Treatment is not required for asymptomatic isolated osteopathic striata.

A genetic basis for congenital pseudarthrosis of the
clavicle is unclear. Most cases are thought to arise sporadically,
although familial cases demonstrating autosomal dominant inheritance
have been reported (235,236).
Congenital pseudarthrosis of the clavicle is thought to occur either
because of a primary intrinsic failure of clavicular development or
because of external compressive forces. The development of the clavicle
from two separate centers of intramembranous ossification was first
recognized by Mall (236) and has been confirmed by others (237,238).
It has been postulated that an intrinsic failure of coalescence of
these two centers is responsible for the development of pseudarthrosis (239). Lloyd-Roberts et al. (158)
postulated that extrinsic compression by the subclavian artery, alone
or in combination with a cervical rib, was responsible for the defect.
This interesting concept is supported by the overwhelming frequency of
right-side involvement, the normally higher location of the right
subclavian artery compared to the left, and the location of the artery
directly under the area of the defect. Rare cases of left-side
involvement have been associated with dextrocardia, and bilateral cases
have been associated with cervical ribs (240).

Congenital pseudarthrosis of the clavicle typically
presents in infancy or in early childhood, with a painless prominence
and hypermobile segment over the middle third of the clavicle.
Radiographs may be necessary to distinguish the lesion from birth
fracture or cleidocranial dysplasia. Most lesions involve only the
right clavicle, although bilateral cases and rarer left-side cases have
been described. The cosmetic deformity tends to be slowly progressive,
with an increase in noticeable prominence over the pseudarthrosis and
foreshortening and dropping of the shoulder girdle over time. The
pseudarthrosis can become painful with certain overhead activities, or
with direct compression or palpation. Shoulder motion is typically
regarded as normal, and significant functional disability is unusual.
Several cases of later development of thoracic outlet compression
syndrome have been reported in association with congenital
pseudarthrosis of the clavicle (235,241,242,243,244,245,246,247,248).

The radiographic findings in congenital pseudarthrosis
are characteristic. The clavicle typically displays a definite
separation in its midportion, with the medial aspect lying superior to
the lateral aspect, owing to muscle forces and the weight of the upper
extremity. The bone ends appear bulbous, with sclerotic closure of the
marrow cavity and no evidence of callus formation or reactive bones (Fig. 10.14A). The disorder is

easily distinguishable from cleidocranial dysplasia because of the lack
of other characteristic radiographic abnormalities of the skull and
pelvis, including wide cranial sutures, coxa vara, failure of pubic
ossification, and hypoplastic ilia. Subsequent radiographs of the
clavicle will fail to demonstrate callus formation, thereby
distinguishing early cases from acute neonatal fracture.

Histopathologic specimens from resected lesions have
demonstrated hyaline cartilaginous caps at both ends of the
pseudarthrosis, often joined by dense fibrous and fibrocartilaginous
tissue (249,250).
Hirata et al. demonstrated columnar distribution of chondrocytes in
different stages of maturation at the ends of the pseudarthrosis,
similar to that seen in a developing cartilaginous physis. Endochondral
ossification at these terminal ends was confirmed by tetracycline
labeling (251).

Most patients with congenital pseudarthrosis of the
clavicle, whose cases are described in the literature, have undergone
some form of operative treatment, and therefore the true natural
progression of untreated cases is unknown. Indications for operative
management have included progressive pain and unacceptable cosmetic
deformity at the site of the pseudarthrosis, functional limitations
and, at later stages, onset of thoracic outlet compression syndrome (235,239,241,242,243,244,245,246,247,248,249,251,252,253).
Most specialists recommend delaying surgery until the patient is
approximately 3 to 6 years of age, and thereafter resecting the
pseudarthrosis followed by bone grafting and internal fixation, most
commonly with the use of a plate and screws (235,238,244,250,253) (Fig. 10.14B).
Solid union of the pseudarthrosis and acceptable cosmesis have been
regularly achieved by using these methods. Grogan et al. reported on
early operative treatment of this condition in eight patients, of whom
six were younger than 30 months (252). They
demonstrated union in all eight patients, using a technique of careful
preservation of the periosteal sleeve, resection of the pseudarthrosis,
and approximation of the bone ends without bone grafting or internal
fixation. Toledo and MacEwen pointed out the hazards of using an
intramedullary pin for fixation after operative treatment of this
condition (254), although this technique has been successfully employed by others (250,255).

We recommend surgical treatment of congenital
pseudarthrosis using a technique of resection of the pseudarthrosis,
autogenous iliac crest grafting, and plate and screw fixation,
typically performed at approximately 3 to 6 years of age. This approach
avoids the noticeable clavicular prominence and foreshortening and
dropping of the shoulder girdle that occurs over time, and it may
eliminate the later development of thoracic outlet syndrome, although
this is unsubstantiated. Parents should be counseled that operative
treatment does replace a “bump” with a “scar,” and is not essential for
ensuring good shoulder function.

The etiology of dysplasia epiphysealis hemimelica is
unknown. Trevor considered it to be a congenital error of skeletal
development, in which an altered process of cell division at the
superficial zone of articular cartilage allows for persistent
proliferation and production of a large cartilaginous mass (257).
Fairbank hypothesized that the disorder was due to a localized
disturbance of the pre- or postaxial part of the apical cap of the limb
bud in early fetal development (258). To date, no clear mechanism for genetic transmission of the disorder has been described.

The incidence of the disorder has been estimated at 1 in
1 million, most of them being men. Presentation is usually in childhood
or early adolescence, although presentations in adulthood have also
been described (259). In cases of multiple
sites of involvement, the lesions are characteristically unilateral,
although bilateral cases have been reported. Azouz et al. classified
dysplasia epiphysealis hemimelica into three categories: (i) localized
(involving only one epiphysis), (ii) classic (involving more than one
bone in a single limb), and (iii) generalized (involving an entire
lower extremity from the pelvis to foot). The classic form is the most
common (260). Clinical features vary, depending
on the location of the lesion, but patients typically complain of
painless swelling or a mass on one side of a joint, limitation of
motion, and occasionally locking, angular deformity, limp, regional
muscle wasting, or limb-length discrepancy. The lower extremities are
affected most commonly, predominantly at the knee and ankle (257,258,261,262).
Other reported sites have included the capital femoral epiphysis and
acetabulum, sacroiliac joint, metacarpophalangeal joint, wrist,
shoulder, and subtalar joint (263,264,265,266,267,268,269).

The radiographic features of dysplasia epiphysealis
hemimelica can vary depending on the age of the patient and the degree
of maturation of the lesion. The radiologic diagnosis is fairly
straightforward when the lesion is fully calcified or ossified,
appearing as an irregular, often multicentric, lobulated mass
protruding directly from one side of the affected epiphysis or tarsal
bone (Fig. 10.15). The affected ossification
center will often appear prematurely, and may be larger than the
contralateral side. Modeling abnormalities of the adjacent metaphysis
have also been reported. However, early lesions may present only with
joint space enlargement or small foci of irregular calcification, and
may resemble para-articular tumors or other disorders that involve
ectopic ossification or calcification. With maturation, the lesion
enlarges and ossifies, and becomes confluent with the underlying
epiphyseal bone (270). MRI has proven useful in
demonstrating the extent of the lesion and in identifying a potential
cleavage plane between the lesion and the underlying epiphysis (261,270,271,272).

On gross and microscopic examination, the lesion will
resemble an osteochondroma, although no discrete stalk is present.
Microscopically, one may find a boundary of cartilage separating the
lesion from the underlying bony epiphysis, if the lesion has not yet
fully ossified. A thick zone of hyperplastic cartilage is
distinguishable from the rest of the cartilaginous epiphysis only by
some irregularity in the size and distribution of the chondrocytes (258). Malignant degeneration of the lesion has not been reported.

Treatment of dysplasia epiphysealis hemimelica should be
directed at addressing the patient’s complaints, while preserving the
integrity of the affected joint as much as possible. Most of the
reported cases have been treated surgically, and therefore the
long-term prognosis for untreated lesions involving the weight bearing
surface of the joint (i.e., articular lesions) is mostly unknown.
Fairbank predicted that the affected joints would go on to early
degenerative joint disease, and this has been demonstrated in some
patients after surgical intervention (261,262,267,273).
If the cartilaginous overgrowth is not on the weight bearing surface of
the joint (i.e., juxta-articular lesions), simple excision is warranted
in order to relieve pain and improve function. However, recurrence of
the lesion prior to skeletal maturity has been reported (262,263).
Fairbank described spontaneous correction of associated angular
deformities after excision, but this has not been a consistent finding (236).
The treatment of articular lesions remains somewhat controversial. Kuo
et al. did not recommend excision of articular lesions because of
unsatisfactory results in three of nine patients with lesions involving
the distal tibia and talus (262). Keret et al.
performed corrective osteotomies without excision for angular deformity
associated with articular lesions wherever an arthrogram demonstrated a
smooth joint surface (261). The authors noted
recurrence of valgus deformity at the knee after varus osteotomy in one
of three patients, requiring repeat osteotomy.

MRI is utilized to evaluate the articular surface of the
affected joint and to identify any potential cleavage plane for
surgical separation of the lesion from the underlying epiphysis.
Symptomatic juxta-articular lesions are treated by simple excision.
Intra-articular lesions are treated by excision if there is
irregularity of the articular surface. Close observation of limb length
and alignment is necessary in view of the potential for growth arrest
and angular deformity, and osteotomy and/or limb lengthening may be
required.

The genetic defect and pathophysiology responsible for
fibrodysplasia ossificans progressiva are unknown at this time, and
clinical, molecular, and genetic heterogeneity may exist (279,280,281).
The combination of the congenital malformation of the great toe and the
postnatal development of heterotopic bone, in characteristic patterns
of developmental gradients, suggests a possible role of the bone
morphogenetic proteins in the etiology of this disorder. Bone
morphogenetic proteins have been implicated in several embryonic
epithelial and mesenchymal interactions, such as limb formation, and
have the potential to transdifferentiate myoblasts in culture into
osteoblastlike cells. Overexpression of bone morphogenetic protein 4
(BMP 4) and its messenger ribonucleic acid (mRNA), and elevated steady
state levels of BMP 4 receptor mRNA, have been demonstrated in lesional
and nonlesional tissue from patients with this condition (282,283,284). However, a mutation in the BMP 4 gene has not been demonstrated.(285).

Additionally, high-affinity antagonists of BMP 4, such as the secreted
polypeptide noggin, are underexpressed in the cells of affected
patients (286),
thereby suggesting that an impaired BMP-antagonist response following
soft-tissue trauma could explain the explosive bone induction seen
during flare-ups.

The earliest recognizable manifestation of
fibrodysplasia ossificans progressiva involves aberrant morphology of
the great toe, which demonstrates shortening of the first ray,
delta-shaped proximal phalanx, interphalangeal joint fusion, and
varying degrees of hallux valgus, either alone or in combination (287).
Progressive heterotopic ossification becomes evident at a mean age of 5
years, but may be seen shortly after birth or as late as the second
decade of life. Most lesions arise spontaneously, although blunt trauma
can trigger the onset. Individual nodules can regress, although most of
them progress to form mature bone. In their review of 44 patients with
fibrodysplasia ossificans progressiva, Cohen et al. noted a predictable
pattern of involvement of heterotopic ossification, proceeding from
axial to appendicular, cranial to caudal, and proximal to distal (288).
Dorsal involvement preceded ventral involvement, with the initial
lesion characteristically occurring as a painful, erythematous,
subfascial nodule in the posterior aspect of the neck, spine, or
shoulder girdle. Kaplan et al. described the early, intermediate, and
late progression of a typical lesion in fibrodysplasia ossificans
progressiva (277). The early lesion is heralded
by pain, erythema, swelling, warmth, and tenderness, and may resemble
an infectious process. After several weeks, the swelling and pain begin
to subside, but an increase in induration occurs (the intermediate
lesion). The late lesion is present by 12 weeks, and consists of a
hard, painless mass that is evident roentgenographically (Fig. 10.16).

Severe disability ensues secondary to extra-articular
ankylosis of the major diarthrodial joints. Hip and knee involvement
can impair walking and sitting ability. Progressive spinal deformity is
common, and can be particularly severe when unilateral
pelvis-to-chest-wall synostosis is present (289). Humeral-to-chest-wall synostosis can lead to superior subluxation of the glenohumeral joint (290).
Involvement of the temporomandibular joint may lead to inanition with
resultant poor nutrition. Decubiti often develop because of a
combination of underlying bony prominences, poor nutrition, and lack of
mobility. Other characteristics that may be associated with this
disorder include shortened thumbs, fifth-finger clinodactyly,
conductive hearing loss, diffuse thinning of the hair on the scalp,
premature cessation of menses in female patients, and, uncommonly,
mental retardation. Exacerbating factors may include trauma to the
muscles, biopsy of lesions, surgical attempts at bone removal,
intramuscular injections, careless venipuncture, and dental therapy (287).
New lesions can occur throughout the patient’s lifetime, and most
patients become completely immobilized and confined to a wheelchair by
their third decade. The diaphragm, extraocular muscles, cardiac muscle,
and smooth muscle are characteristically spared in the disorder.

Cardiopulmonary dysfunction can play a role in the
shortened survival of some patients with fibrodysplasia ossificans
progressiva. Heterotopic ossification involving the chest wall and
spine can lead to impaired chest wall dynamics and reliance on
diaphragmatic breathing (278,288).
Kussmaul et al. found a high incidence of right ventricular
abnormalities on electrocardiographic evaluation of patients with
fibrodysplasia ossificans progressiva who had severely restrictive
chest-wall disease (291). The investigators raise the possibility that cor pulmonale could eventually develop in such patients.

The areas of heterotopic ossification in fibrodysplasia
ossificans progressiva are initially similar in radiographic appearance
to myositis ossificans, with diffuse calcification developing
progressively to zonal osseous maturation. Sheets of mature skeletal
bone eventually form along striated muscles, fasciae, tendons, and
ligaments, causing ankylosis of the joints. Solid extraosseous bridges
can form between bones, leading to characteristic synostoses of
cervical spine to occiput, of scapula and chest wall to humerus, of
spine to pelvis, and of pelvis to femur. In addition to the
characteristic great toe deformities, abnormal cervical vertebrae with
small bodies, large posterior elements and fused lateral masses,
shortened first metacarpals, fifth-finger clinodactyly, short and broad
femoral necks, and exostoses of the proximal tibiae have been reported (Fig. 10.16 C,D,E,F) (287).

Erroneous results of biopsies of the lesions in case of
fibrodysplasia ossificans progressiva have provided insights into the
pathogenesis of the ossification. Histopathologic and
immunohistochemical studies of specimens from early preosseous lesions
reveal an abundance of primitive vascular cells and angiogenesis, with
a conspicuous absence of an acute or chronic inflammatory process. The
clinician may be misled toward a presumptive diagnosis of aggressive
fibromatosis or low-grade sarcoma at this stage if fibrodysplasia
ossificans progressiva is not considered. Intermediate lesions exhibit
scattered cartilaginous foci and evidence of endochondral ossification,
the stages proceeding in a sequence that appears entirely normal. Late
lesions demonstrate histologically normal lamellar bone, with fatty
marrow encased in fibrous connective tissue (292).

There is presently no effective treatment for
fibrodysplasia ossificans progressiva. Treatment is largely supportive,
with attempts at limiting the factors that exacerbate ectopic bone
formation, such as trauma, intramuscular injections, careless
venipuncture, and dental extractions. Padding of bony prominences and

nutritional
support may be useful in preventing decubiti. Biopsy of lesions or
surgery to excise ectopic bone must be avoided, because they always
precipitate new bone formation (287).

The administration of high doses of oral diphosphonates
and corticosteroids has not been shown to influence the development of
the ectopic ossifications. Brantus and Meunier evaluated the effects of
intravenous administration of ethane-1-hydroxy-1-diphosphonate and oral
prednisone on early flare-ups in patients with fibrodysplasia
ossificans progressiva (293). During a mean
follow-up of 6 years in 7 patients with the disorder, the symptoms of
local swelling and pain were ameliorated in 29 out of 31 acute
flare-ups, and no ossification appeared in 21 flare-ups. However, the
percentage of acute flare-ups that normally result in ossification is
unknown; therefore it cannot be confirmed whether administering
intravenous diphosphonates during early flare-ups has any effect on
subsequent progression to ossification. Also, during the period of
study, 10 new ossifications were observed that resulted in severe
deterioration of joint mobility, and there was no change in the
radiographic appearances of preexisting ossifications.

In the future, medical therapies for fibrodysplasia
ossificans progressiva will likely center around inhibitors of
endochondral osteogenesis. Proposed treatments have included the use of
BMP 4 inhibitors, isotretinoin (an
inhibitor of mesenchymal tissue differentiation into cartilage and
bone), and antiangiogenic and antiinflammatory factors (293,294,295,296,297). To date, such treatments should be regarded as investigational.