A family with dominant endosteal hyperostosis was described by
the senior one of us (R.K.B.) in 19761.
The propositus was a sixty-four-year-old man who had a cemented
total hip replacement for the treatment of arthritis that had developed
after a traumatic hip dislocation without a fracture. The finding
of widespread increased density of the skeleton led to the evaluation
of multiple family members. The pedigree demonstrated four generations
with affected members. Eight members were examined clinically and
radiographically. The affected individuals among the remainder were
identified on the basis of family reports as the facial features
of individuals with the disorder are quite distinctive. These features
are not present until early adulthood so it was not possible to
determine with certainty the affected members in the most recent
generation. Evaluation of the first three generations indicated
that eleven of the twenty-five offspring of affected parents were
affected, and the pattern of inheritance included male-to-male transmission.
This finding suggests autosomal dominant inheritance and is compatible
with findings in previous reports on this condition. The patient willed
his body for study following his death.
Autosomal dominant endosteal hyperostosis was first described
by Worth and Wollin, in 19662.
The dysplasia is characterized by normal stature and intelligence.
The age at which it can be diagnosed is not known, but facial changes
and diaphyseal radiographic changes are present by adolescence.
The facial changes include elongation of the mandible and an increased
gonial angle. The forehead becomes flattened. There is a slowly
enlarging osseous prominence of the hard palate (torus palatinus).
The enlarging mandible and the development of a torus palatinus
in the hard palate contribute to malocclusion and loss of teeth.
The early radiographic changes include thickening of the endosteum
of the long bones and of the skull. There is a gradual increase
in density of the posterior elements of the spine, which may be associated
with arthritis and may lead to nerve entrapment3.
Foraminal encroachment involving the facial, auditory, and optic
nerves does not normally occur. Serum calcium, phosphorus, and alkaline
phosphatase levels are normal. The limbs are asymptomatic and without
deformity. The clinical prognosis for dominant endosteal hyperostosis
is generally good despite widespread increased bone density.
In a review of the literature, we found reports1-12 on thirteen kindreds with endosteal
hyperostosis, which has been given a variety of names since it was
first described in 1966. Of the thirteen kindreds, eleven demonstrated
dominant inheritance while two were sporadic cases. Four of the
eleven kindreds had male-to-male transmission, indicating autosomal dominant
inheritance. The investigators reported torus palatinus in seven
of the thirteen kindreds, did not comment on it in five, and stated
that it was not present in one. Spinal stenosis was not reported,
although the thickening of the posterior facet joints suggests that
possibility. The bones of patients with endosteal hyperostosis are
heavier than normal. Several affected patients in the present kindred
and in others reported difficulty while swimming because of a lack
of buoyancy3. The affected bones
in patients with endosteal hyperostosis are resistant to fracture.
None of the patients in the present kindred have had a fracture
despite active lifestyles. Only two patients with a fracture have
been reported in the literature: an eighty-five-year-old man who
had a hip fracture and a fifteen-year-old boy who sustained a tibial
fracture while skiing2,6. The
histological and biomechanical properties of bone in this dysplasia
have not been previously described.
This condition is to be differentiated from the recessive form of
endosteal hyperostosis described by Van Buchem13.
Van Buchem dysplasia, which occurs less commonly than dominant endosteal
hyperostosis, is seen primarily in the Dutch population and is transmitted
by autosomal recessive inheritance. Van Buchem dysplasia is evident
in childhood, is more disabling than dominant endosteal hyperostosis,
and commonly involves the cranial nerves, with facial palsy or deafness
found in more than half of those affected. It is not associated
with a torus palatinus. Beighton et al. suggested that Van Buchem
dysplasia, which is seen in the Dutch population, and sclerosteosis,
which is seen in the South African population, may both be the consequence
of homozygosity for the same pair of abnormal genes14. Recent studies15,16 have
shown that Van Buchem disease and sclerosteosis are localized to
the same region on chromosome 17.
Two other dominantly inherited dysplasias with increased bone
density that may be confused with endosteal hyperostosis are Engelmann
disease and osteopetrosis. Engelmann disease has its onset in childhood,
is associated with muscle weakness, and often causes enlargement
of the metaphysis; it does not cause the jaw changes or the torus
palatinus seen in endosteal hyperostosis. The late-onset form of
osteopetrosis is characterized by a uniform increase in bone density
in the pelvis and ribs, frequent occurrence of "sandwich" layers
of increased density in the vertebrae and long bones, and an increased
prevalence of fractures and anemia.
The spinal changes in endosteal hyperostosis may also be confused
with diffuse idiopathic skeletal hyperostosis. The latter disorder
is characterized by osseous proliferation at sites of ligamentous
attachments and often by ossification of the posterior longitudinal
ligament of the cervical spine and extensive hypertrophic osteophytes
of the spine. Affected patients do not have the characteristic facial
features or the selective increase in the density of the posterior
elements of the spine that are seen in endosteal hyperostosis.
The donated skull, spine, humeri, ulnae, femora, tibiae, and hand
and tarsal bones of the propositus were studied. The bones were
wrapped in cloths soaked in 0.9% saline solution, placed
in double plastic bags, and frozen at —20°C until tested. The
biomechanical findings in the skeleton of the propositus were compared
with those in the humeri, femora, and tibiae from an age-matched
man who had died of cardiac failure. Neither the propositus nor
the normal donor was obese, but their heights and weights were not
precisely matched. Specimens were obtained from the same sites and
in an identical manner and were tested with use of identical methods.
Radiographs were made of the long bones, hands, feet, spine, pelvis,
and skull. Computed tomography scans were made of the spine and
skull.
Samples of cancellous and cortical bone were obtained from comparable
sites in the normal bones and in those with endosteal hyperostosis,
were fixed in 10% neutral buffered formalin, and were decalcified
with use of dilute hydrochloric acid (Decal Stat; Decal Chemical,
Congers, New York). Bone sections, 4 mm thick, were cut and were
stained with hematoxylin (Fisher Diagnostics, Fairlawn, New Jersey)
and eosin. Cross-sectional whole mounts of the femoral diaphysis
of the propositus and of the matched normal donor were prepared for
histological examination.
Cortical specimens from the middle part of the femur and the middle
part of the humerus were tested for stiffness and strength, allowing
comparison of the biomechanical properties of both weight-bearing
and non-weight-bearing long bones. Rectangular sections of uniform
dimensions (75 ¥ 3 ¥ 3 mm) were obtained with
use of a bone saw (Exakt; Exakt Technologies, Hamburg, Germany).
Care was taken to ensure parallelism of all sides and equal side
dimensions. Six, seven, or eight cortical specimens per bone were
obtained from each section. The specimens were bathed in saline
solution during cutting and were wrapped in saline-solution-soaked
gauze until tested.
Each cortical bone specimen was loaded in bending with use of
a standard three-point bending fixture to determine the flexural
elastic modulus (stiffness) and breaking strength. The specimens
were placed on a three-point loading fixture with supports located
50 mm apart with a central bending load applied. Each specimen was
cycled through five cycles to 2% of estimated failure load
to reduce viscoelastic material behavior. The specimens were then
loaded at a rate of 1 mm/min. The central deflection of
each specimen and load were recorded at 10 Hz throughout the test.
A materials testing machine (Mini Bionix; MTS Systems, Eden Prairie,
Minnesota) was used for all mechanical tests. The bending modulus was
calculated for each specimen17.
The specimen was tested once in a direction radial to and again
in a direction circumferential to the axis of the bone18-20.
Statistical analyses were conducted to determine differences in
the elastic modulus of the humeri and femora with use of a two-way
analysis of variance with the significance level set at p = 0.05.
Specimens of cancellous bone were obtained from the proximal
tibial metaphysis to test for stiffness and strength. A 3-cm-thick
slice of bone, containing cortical bone around the periphery and
cancellous bone in the center, was removed. The proximal surface
was sequentially sawed in thin slices until all of the articular
surface and cortical bone were removed. The block was then sectioned
into small cancellous bone cubes (5 5 5 mm) with use of the bone
saw. Specimens containing any cortical bone were discarded. Care
was taken to ensure parallelism of all sides. Each cancellous cube was
defatted with pressurized water and placed in a bath of saline solution
until testing.
The cancellous bone specimens were loaded in compression with
use of an unconstrained compression test to determine the compressive
elastic modulus, compression strength, and maximum compressive displacement
of each specimen18. The specimens
were centrally placed on a loading platen, which articulated with
the load-cell through a universal joint, ensuring uniaxial loading.
Each specimen was loaded at a rate of 1 mm/min in compression
until 50% of the initial height was reached. Force and
displacement data were collected at 10 Hz. We attempted to control
for variable architecture by measuring specimens of the same size,
obtained from the same anatomic site, and tested in the same anatomic
direction21,22.
The biomechanical properties of bone are highly dependent on
the density and architecture of the tissue19,23-25.
The density of the tissue was measured by determining the ash weight.
The specimens were placed in a furnace at 700C for eighteen hours
to remove the organic components. The fraction of remaining substance
after ashing was divided by the original weight to determine the
mineral fraction.
Radiographic Examination
Postmortem radiographs of the long and short bones of the extremities
affected by endosteal hyperostosis demonstrated thick, dense endosteal
bone in the diaphysis. The medullary canals were narrow but patent,
and the endosteal surface was not uniform. The tarsal and carpal
bones demonstrated thick and irregular trabeculae (Figs. 1 and 2). The vertebrae demonstrated
increased density, coarse trabeculae, and large osteophytes. The
posterior elements were more dense than the vertebral bodies. There
was spontaneous fusion in segments of the cervical, thoracic, and
lumbar vertebrae (Fig. 3). Computed tomography scans of
the spine demonstrated that the vertebral laminae were thick with
enlarged, arthritic facet joints. The pelvis had coarse trabeculae
and increased density in the periacetabular region. The cortex of
the skull was very thick. The mandible was edentulous and elongated,
and it had an increased gonial angle (Fig. 4). The torus palatinus was prominently
demonstrated on the computed tomography scan (Fig. 5).
Histological Evaluation
Sections of the metaphyseal and diaphyseal regions of the humerus,
femur, and vertebrae were stained with hematoxylin and eosin and
examined histologically. The diaphyseal cortex of the bone with
endosteal hyperostosis demonstrated marked thickening compared with
that in the normal specimen, but the haversian systems and cement
lines showed a normal arrangement. The trabeculae of the cancellous
bone of the vertebrae with endosteal hyperostosis were thicker than
normal, but the architectural features were normal. The whole mounts
of the femora with endosteal hyperostosis demonstrated marked endosteal
thickening of the cortical bone in the diaphysis (Figs. 6-A, 6-B, and 6-C).
Mechanical Testing and Mineral Density
The cortical bone of both the femur and the humerus with endosteal
hyperostosis was found to be stiffer than that of the normal femur
and humerus (p < 0.05). Post hoc testing
with use of the Bonferroni test demonstrated that the stiffness
of the normal femur was not significantly different from that of
the normal humerus26. The radial
stiffness of the humerus with endosteal hyperostosis was significantly
greater than that of the normal femur and humerus. The radial stiffness
of the femur with endosteal hyperostosis was significantly greater
(p £ 0.05) than that of the normal humerus but not greater
than that of the normal femur (Table I).
The compressive stiffness of the cancellous bone of the tibia with
endosteal hyperostosis was not significantly different from that
of the normal tibia. The mean maximum compressive load of the tibia
with endosteal hyperostosis was significantly higher than that of
the normal tibia (p £ 0.05) (Table II).
The percent ash weight of the cortical bone of the femur with endosteal
hyperostosis was not found to be different from that of the normal
femur. The normal humerus had a significantly lower percent ash
weight than the humerus with endosteal hyperostosis had (p £ 0.05)
(Table III).
The percent ash weight of the cancellous bone of the normal tibia
was significantly lower than that of the tibia with endosteal hyperostosis
(p £ 0.05) (Table II).
Endosteal hyperostosis may be more common than is implied by
the few reports on it in the literature, as two additional kindreds
with this disorder have been identified by the senior one of us
(R.K.B). The original diagnosis in these patients had been osteopetrosis.
The initial radiographic feature of this dysplasia is hyperostosis
of the endosteal surface of the diaphysis of the long bones combined
with involvement of the skull and mandible. With advancing age,
the trabeculae of the metaphysis become thickened. The age when
torus palatinus appears has not been documented, but it may prove
to be a good clinical determinant of involvement in patients who
are at risk for the disorder.
The factors that contribute to the stiffness of bone include
the quality, quantity, and architecture of the tissue. Quality was assessed
through biomechanical testing, quantity was assessed by measuring
ash weight, and architecture was assessed histologically.
Biomechanical testing revealed that both cortical and cancellous
bone in patients with endosteal hyperostosis were stiffer than normal
bone. We contrasted the biomechanical properties of the bone in
the skeleton of a patient with endosteal hyperostosis with those
of the bone in only one normal skeleton. Testing multiple skeletons
might produce somewhat different results.
Both ash weight and strength (maximum load) were increased in
weight-bearing and non-weight-bearing bones in the patient with
endosteal hyperostosis compared with those in the normal skeleton.
The mineral ash weight of cortical bone in endosteal hyperostosis
was similar to that of normal bone, whereas the ash weight of cancellous
bone in endosteal hyperostosis was increased compared with that
of normal bone.
Histological evaluation demonstrated that the metaphyseal trabeculae
in the bone with endosteal hyperostosis were thicker than those
in the normal bone. Cortical thickness was also greater in the bone
with endosteal hyperostosis compared with that in the normal bone.
The cellular architecture was normal.
In this dysplasia, the bones are neither increased in size nor deformed
as they are in Paget or Engelmann disease, and they are not prone
to fracture as they are in Paget disease and osteopetrosis. None
of the patients in the three large kindreds that we examined have
had fractures despite active lifestyles, and only two fractures
have been reported in the literature. Indeed, this dysplasia appears
to offer protection from fracture. It is interesting to speculate
that localization and characterization of the causative gene may
provide useful information on how to enhance bone strength in conditions
in which it has been weakened.
In conclusion, dominant endosteal hyperostosis becomes clinically
and radiographically evident by adolescence, does not cause deformity
except in the skull and mandible, and is not associated with bone
pain or fracture. The initial radiographic changes are thickening
of the endosteal surface of the long bones. The osseous changes
are slowly progressive and eventually affect cancellous bone in
older patients. Arthritic changes associated with foraminal encroachment
in the spine as well as facial and jaw changes slowly progress in
adulthood. Endosteal hyperostosis does not appear to affect longevity.
Biomechanical testing indicates that there is increased strength
of cortical and cancellous bone. This dysplasia appears to offer
some protection against fracture.