Sclerosing bone dysplasias are rare genetic disorders characterized by the creation of abnormally dense and overgrown bones. The abnormal bone formation in sclerosing bone dysplasias is caused by a defect in the replacement of old bone with new bone.
Description
Bone consists of living cells, called osteocytes, embedded in a calcium carbonate matrix that makes up the main bone material. The calcium carbonate matrix includes inorganic mineral components like calcium and organic components, such as collagen. The replacement of old bone with new bone is mediated by two types of bone cells, osteoblasts and osteoclasts. The osteoblasts make bone, while osteoclasts resorb, or take away, bone. Problems with the ability of the osteoclasts and osteoblasts to remodel bone can result in the increased skeletal density (sclerosis) and bony overgrowth (hyperostosis) seen in the sclerosing bone dysplasias. The first description of sclerosing bone dysplasia occurred in 1904 when Professor Albers-Schnberg of Hamburg described a patient suffering from a benign form of thickened and very strong hard bone.
Currently, sclerosing bone dysplasias are subdivided into types based upon the problems in bone remodeling. The three main categories of sclerosing bone dysplasias are: increased bone density without modification of bone shape; increased bone density with involvement of main body of the bone and primary region of bone formation (diaphysis); and increased bone density with involvement of the area of the developing long bone that is the growing portion of the bone (metaphysis). Although all of the sclerosing bone dysplasias share some overlapping features, it is usually possible to distinguish between these types of sclerosing bone dysplasia based on the age at which symptoms appear, the pattern of inheritance in the family, radiographic skeletal surveys, and genetic studies.
Genetic profile
Although all of the genes involved in sclerosing bone dysplasias encode proteins that direct the remodeling of bone, each type of sclerosing bone dysplasia has specific symptoms and inheritance patterns caused by different gene defects.
Many types of sclerosing bone dysplasia are autosomal dominant genetic disorders. In autosomal dominant genetic disorders, the genes that cause a particular disorder are carried on one of the 22 pairs of numbered autosomal chromosomes, rather than on the X or Y sex chromosomes. In the case of sclerosing bone dysplasia, only one copy of the mutated, or nonworking, gene is necessary for the development of the disorder. An individual who inherits a normal gene copy from one parent and an abnormal gene copy from the other parent is likely to have symptoms of a sclerosing bone dysplasia. The children of an individual with one normal gene copy and one mutated copy have a 50% chance of inheriting the disorder. Types of sclerosing bone dysplasias inherited in an autosomal dominant pattern include: benign dominant osteopetrosis (caused by a mutation in the chloride channel 7 gene, ClCN7); progressive diaphyseal dysplasia (caused by a mutation in the beta-1 transforming growth factor gene, TGFB1); some forms of craniodiaphyseal dysplasia; Van Buchem disease, type II (caused by a mutation in the low-density lipoprotein receptor-related protein 5 gene, LRP5); and some forms of craniometaphyseal dysplasia (caused by a mutation in a multipass transmembrane protein, ANK).
Many other types of sclerosing bone dysplasia are inherited in an autosomal recessive pattern. In an autosomal recessive condition, two copies of the mutated gene are needed to develop the symptoms of the disorder. In these cases, both parents each carry one copy of a mutated gene. Individuals with only one copy of a mutated gene for a recessive condition are known as carriers and have no symptoms related to the condition. In fact, every person carries between five and 10 mutated genes for harmful, recessive conditions. However, when two people with the same mutated recessive gene for sclerosing bone dysplasia have children together, there is a 25% chance with each pregnancy for the child to inherit two mutated copies, one from each parent. That child then has no working copies of the gene and will display the signs and symptoms associated with sclerosing bone dysplasia. Sclerosing bone dysplasias that are inherited in an autosomal recessive manner include: malignant infantile osteopetrosis (caused by mutations in the ATP6i/TCIRG1, CLCN7, and GL genes); pycnodysostosis (caused by mutations in the cathepsin K gene, CATK); some forms of craniodiaphyseal dysplasia; Van Buchem disease, type I (caused by mutations in VBCH, 17q11.2); sclerosteosis (caused by a mutation in the sclerostin gene, SOST); and some forms of craniometaphyseal dysplasia.
One type of sclerosing bone dysplasia, frontometaphyseal dysplasia, is caused by a mutation in the filamin A gene (FLNA) and is inherited in an X-linked recessive pattern. As opposed to genes that are carried on one of the 22 pairs of numbered autosomal chromosomes, X-linked genes are found on the sex chromosomes called X. Females have two X chromosomes, while males have a single X chromosome and a single Y chromosome. When a female inherits a mutated gene on the X chromosome, she is known as a carrier. Carriers most often have no symptoms related the condition because the gene on her other chromosome continues to function properly. However, males only inherit one copy of the information stored on the X chromosome. When a male inherits a mutated copy of the gene that causes an X-linked recessive condition, he will experience the symptoms associated with the disease. The chance for a carrier female to have an affected son is 50%, while the chance to have a daughter who is also a carrier for the condition is 50%. An affected male has a 100% chance of having carrier daughters and a 0% chance of having affected sons.
One type of sclerosing bone dysplasia, osteopathia striata with cranial sclerosis, is inherited in an X-linked dominant pattern. X-linked dominant inheritance occurs when the gene is located on the X chromosome, but the gene acts in a dominant manner. This means that both males and females can display the trait or disorder, while having only one copy of the gene. Furthermore, in X-linked dominant conditions, only one copy of the mutated gene is necessary for the development of the disorder. Therefore, an individual who inherits a normal gene copy from one parent and an abnormal gene copy for sclerosing bone dysplasia from the other parent is likely to have symptoms of sclerosing bone dysplasia. The children of an individual with one normal gene copy and one mutated copy have a 50% chance of inheriting a mutated sclerosing bone dysplasia gene.
Demographics
Sclerosing bone dysplasias are rare conditions. Estimates of general population frequency range by ethnic group and type of sclerosing bone dysplasia described. Affected individuals can occur within a variety of ethnic backgrounds and cases have been found in countries, including Denmark, Egypt, the United States, Germany, Japan, Italy, Brazil, Spain, Senegal, South Africa, the Netherlands, and Cyprus. A large number of individuals affected by sclerosing bone dysplasias exist in the Afrikaner population of South Africa and the Dutch population of the Netherlands. The carrier rate for the single founder-derived mutation that causes sclerosteosis in the Afrikaner population is approximately one in 100. Van Buchem disease has been recognized predominantly in the Dutch population (±20 cases). Several of the affected families have ancestral origins on the former island of Urk in the Zuider Zee. The prevalence of later onset osteopetrosis or Albers-Schonberg is about one in 18,000 in Denmark.
Signs and symptoms
Sclerosing bone dysplasias are rare genetic disorders characterized by increased skeletal density and excessive bone formation, or overgrowth, due to a defect in the method of replacing old bone with new bone (bone remodeling). Each of the three main categories of sclerosing bone dysplasias exhibit different symptoms, including age of onset, skeletal involvement, and prognosis.
The specific disorders in the group of sclerosing bone dysplasias that exhibits increased bone density without modification of bone shape include: osteopetrosis disorders 9autosomal dominant osteopetrosis types I and II and autosomal recessive osteropetrosis); pycnodysostosis; and osteopathia striata with cranial sclerosis.
The osteopetrosis disorders are conditions that involve increased bone density without modification of bone shape. They include two forms of benign dominant conditions known as autosomal dominant osteopetrosis I (ADOI) and autosomal dominant osteopetrosis II (ADOII), and one form of malignant infantile osteopetrosis (MIOP).
Benign dominant or autosomal dominant osteopetrosis (ADO) typically presents in childhood, adolescence, or young adult life with multiple fractures, mild anomalies in head and face proportions, mild anemia, hearing loss, bone inflammation/infection, or increased bone density found on routine x-ray studies. ADO has two distinct subtypes known as types I and II that are distinguished by the location of sclerosis and presence or absence of increased bone fractures.
Autosomal dominant osteopetrosis type I (ADOI or OPTA1) is characterized by a generalized increase in the hardness, thickness, and density of bone tissue (osteosclerosis), most pronounced in the cranial vault. Patients are often asymptomatic, but some suffer from pain and hearing loss. ADOI appears to be the only type of osteopetrosis not associated with an increased fracture rate.
Autosomal dominant osteopetrosis type II (ADOII or OPTA2) is characterized by an increase in the hardness, thickness, and density of bone tissue (sclerosis) predominantly involving the spine, the pelvis, and the skull base. Fragility of bones and dental abscesses are the leading complications. Other symptoms include arthritis of the hip (hip osteoarthritis), bone infections (osteomyelitis), thoracic or lumbar scoliosis, and cranial nerve involvement responsible for hearing loss, bilateral optic atrophy, and/or facial palsy. Although other forms of osteopetrosis are considerably more severe, it has been suggested that the name benign osteopetrosis, previously used for ADOII, is probably incorrect given the complications of the condition.
Malignant infantile osteopetrosis (MIOP) is characterized by a generalized increase in bone density found at or soon after birth. The sclerosis of the bones causes a decrease in size of the bone marrow cavities, a progressively enlarging spleen, low blood iron (anemia), and blood cell production that occurs in other parts of the body (extramedullary haemopoiesis). Additionally, enlarging skull bones compress the optic nerves, auditory nerves, facial nerves, and the foramen magnum (the large hole at the base of the skull that allows passage of the spinal cord). The most frequent presentations in infancy are seizures, low calcium level, convulsions, failure of visual fixation (nystagmus), large spleen and liver (hepatosplenomegaly), and frequent broken bones.
Pycnodysostosis is characterized by an increase in bone density of the skeleton (osteosclerosis), skull deformities, short stature, short limbs, characteristic facial features, and bone fragility. Onset of the symptoms occurs around two or three years of age. Other features of the condition include: separated cranial sutures; large fontanel with delayed closure; obtuse mandibular angle; delayed teeth eruption; enamel hypoplasia; dysplastic acromial ends of the clavicles; frontal bossing; ocular proptosis; and dysplastic nails. Developmental evaluations often indicate normal motor, fine motor-adaptive, language, and personal social abilities.
Osteopathia striata with cranial sclerosis (OSCS) presents with longitudinal striations of dense bone in the long bones and formation of dense bone in the cranial and facial bones in infancy and childhood. The formation of dense bone in the head and face leads to facial disfigurement and to neurological complications, such as deafness due to pressure on cranial nerves. Other features include: a large head (macrocephaly); congenital heart defects, such as aortic stenosis and ventricular septal defects; scoliosis of the back; narrowed visual fields; cleft palate; long fingers; curving of the third to fifth fingers (clinodactyly); clubfoot; facial nerve palsy; and mild mental retardation.
The disorders involving increased bone density with diaphyseal involvement include: progressive diaphyseal dysplasia, or Camurati-Engelmann disease; craniodiaphyseal dysplasia; and endosteal hyperostosis disorders (Van Buchem disease (types I and II) and sclerosteosis).
Progressive diaphyseal dysplasia (PDD), or Camurati-Engelmann disease, is characterized by childhood onset of bone overgrowth (hyperostosis) and increased density (sclerosis) of the diaphyses of the long bones and the skull. Other features may include: a slender build with long limbs; angular profile; prominent bones (asthenic habitus); hearing loss; protruding eyeballs (exophthalmos); optic nerve compression; double vision (diplopia); cavities (dental caries); sclerosis of skull base; lower jaw (mandible) involvement; sclerosis of posterior part of vertebrae (body and arches); scoliosis; progressive diaphyseal widening; thickened cortices; narrowing of medullary canal; erlenmeyer flask defect of the bone; clubfoot (genu varus and valgus deformities); relative muscle weakness, especially in pelvic girdle; atrophic muscle fiber; headaches; delayed puberty; bone marrow hypoplasia; anemia; waddling gait; and leg pain. The most severely affected individuals will have progression of mild skull hyperostosis to severe skull thickening and cranial nerve compression over many years. Presentation of the disease can be very different from one individual to another.
Craniodiaphyseal dysplasia includes a wide variety of symptoms and age of onset from infancy to childhood. Facial and cranial thickening and distortion are particularly striking in this form. The characteristic facial features of craniodiaphyseal dysplasia occur from the overgrowth of bone in the face and skull that results in progressive facial anomalies, a broad nasal bridge, and wide-spaced eyes. Other symptoms of craniodiaphyseal dysplasia, like hearing loss and facial paralysis, are caused by the overgrowth of the skull as it gradually eliminates the perinasal sinuses and the large hole at the base of the skull that allows passage of the spinal cord (foramina of the skull base). Individuals with craniodiaphyseal dysplasia often are affected by mental retardation. Unlike the situation in the craniometaphyseal dysplasias, the long bones do not show metaphyseal flaring, but are shaped like a policeman's nightstick.
Endosteal hyperostosis disorders include Van Buchem disease (types I and II) and sclerosteosis. The two endosteal hyperostosis conditions include many similar features. The two disorders can be distinguished from each other via their different appearance of the bone changes on x ray. Additionally, sclerosteosis includes the presence of asymmetric fusion (cutaneous syndactyly) of the index and middle fingers in many cases, and Van Buchem disease does not.
Van Buchem disease (or hyperostosis corticalis familiaris) is characterized by progressive enlargement of the lower jaw in childhood and symptoms, including hearing loss and facial paralysis, in adulthood caused by the overgrowth of the skull. Van Buchem disease has two distinct subtypes known as types I and II. The subtypes are distinguished by genetic cause, primary location of bone overgrowth, and phosphate levels.
The symptoms of Van Buchem disease type I begin in childhood or puberty and include features resulting from bone overgrowth. Symptoms include: cranial bone overgrowth (hyperostosis) leading to optic nerve compression; hearing loss; headaches; cranial nerve palsy; osteosclerosis; thickened cortex of long bones; and abnormally high blood levels of phosphorous (hyperphosphatasemia).
The signs and symptoms of Van Buchem disease Type II begin in childhood or puberty, and include: enlarged lower jaw bone (mandible); increased skull cap (calvarial) thickness; cranial osteosclerosis; thickened cortices of long bones; and normal alkaline phosphatase levels.
Sclerosteosis is characterized by tall stature, overgrowth of the nasal and facial bones, broad, flat nasal bridge, wide-spaced eyes (hypertelorism), and minor hand malformation, such as finger fusion (syndactyly). Other symptoms may include: small nails (nail dysplasia); square jaw due to overgrowth of the mandible; difficulties in chewing; inability to smell (anosmia); massive bone density (sclerosis) of the long tubular bones, ribs, pelvis, and skull; and multiple cranial nerve involvement resulting in optic atrophy, facial palsy, and trigeminal nerve pain episodes (neuralgia). Facial nerve paralysis may be present as early as birth or develop soon afterwards. Facial palsy and deafness as a result of cranial nerve entrapment often develop in childhood. Increased intracranial pressure may result in sudden death from impaction of the brain stem in the foramen magnum.
The disorders involving increased bone density with metaphyseal involvement include craniometaphyseal dysplasia and frontometaphyseal dysplasia.
Craniometaphyseal dysplasia involves overgrowth bone anomalies that commonly present in infancy. Some of the first indications of a craniometaphyseal dysplasia include breathing difficulties and narrowing nasal passages due to bone overgrowth. The characteristic facial features of craniometaphyseal dysplasia occur from the overgrowth of bone in the face and skull that result in progressive facial anomalies, a broad nasal bridge, and wide-spaced eyes. Other symptoms of craniometaphyseal dysplasia, like hearing loss and facial paralysis, are caused by the overgrowth of the skull as it gradually eliminates the perinasal sinuses and the large hole at the base of the skull that allows passage of the spinal cord (foramina of the skull base). The features of craniometaphyseal dysplasia are more severe than the sclerotic or hyperostotic features, except in the lower jaw where they are less severe than craniodiaphyseal dysplasia.
Frontometaphyseal dysplasia's most striking feature is a characteristic facial appearance that includes a very prominent supraorbital ridge above the eyes resulting from bone overgrowth. In many cases, the prominent ridge may be present at birth, along with a small, pointed chin, wide-spaced eyes (hypertelorism), wide nasal bridge, poor sinus development, clubfoot (coxa valga and genu valgum), and flared metaphyses. Later findings may include: progressive mixed conductive and sensori-neural hearing loss; high palate; teeth issues; mitral valve prolapse; narrow trachea; winged shoulder blade (scapulae); irregular rib contours; "coat hanger" deformity of lower ribs; distended kidneys and ureters (hydronephrosis and hydroureter); scoliosis; cervical vertebral fusion; flared pelvis; elbow contractures; knee and ankle contractures; erlenmeyer-flask appearance of femur and tibia; increased density of long bone diaphyses; finger and wrist contractures; long and wide fingers; partial fusion of the bones of the feet; large feet; overgrowth of hair on the buttocks and thighs; muscle wasting (especially legs and arms); and mental retardation. The skeletal dysplasia and the associated clinical findings show significant variability from affected individual to individual. The syndrome has been suggested to be an allelic variant of the Melnick-Needles osteodysplasty.
Diagnosis
Diagnosis of sclerosing bone dysplasias is most often based upon age of onset, clinical features, radiological evaluation, and family history. Radiologic examination will detect the dense bones (sclerosis) and their locations. Genetic studies may help confirm a diagnosis of a specific sclerosing bone dysplasia, but some affected individuals will not have a genetic mutation that can be identified. In 2005, not all types of sclerosing bone dysplasias have a genetic testing available because some forms of sclerosing bone dysplasia have not yet had a causative gene identified.
Treatment and management
The sclerosing bone dysplasias are genetic disorders and do not have specific therapies that remove, cure, or fix all signs of the disorder. Treatment and management of the sclerosing bone dysplasias focus on treatment of specific symptoms of the condition. Management of patients with sclerosing bone dysplasias requires a comprehensive approach to characteristic clinical problems, including hematologic and metabolic abnormalities, fractures, bone deformities, back pain, bone pain, bone infection (osteomyelitis), hearing impairment, dental issues, short stature, and neurologic symptoms. Surgical intervention may be difficult and prolonged in affected individuals since standard equipment may be too short and not powerful enough to cut through the dense bone. In addition, bone regrowth occurs and may cause recurrence of symptoms after surgery.
Treatment of the hematologic issues found in the sclerosing bone dysplasias is focused on the correction of low blood iron (anemia) and low platelets. In some cases, a steroid, prednisone, may be used to treat both of these conditions. In other cases, transfusions to treat anemia and splenectomy to increase platelets may be recommended. Depending on the form of sclerosing bone dysplasia, treatment to correct hematologic issues may not be effective.
Medical treatment of sclerosis and hyperostosis in sclerosing bone dysplasias is based on efforts to stimulate host osteoclasts to break down bone or provide an alternative source of osteoclasts. Stimulation of osteoclasts has been attempted with calcium restriction and calcitrol, calcitonin therapy, steroids, parathyroid hormone therapy, and interferon. Bone marrow transplant has been used to treat infantile malignant osteopetrosis. Effective therapies for each type of sclerosing bone dysplasia need to be individualized. Many people affected by a sclerosing bone dysplasia will not respond to treatment.
Most treatments protocols for sclerosing bone dysplasias are focused upon the correction of the frequent bones fractures, using splints, casts, and braces. Orthopedic surgery may be needed to correct internal fractures.
Since hearing loss is a common feature of the sclerosing bone dysplasias, formal audiological evaluation is recommended at diagnosis. Hearing loss associated with the sclerosing bone dysplasias can be addressed through sign language, use of hearing aids, and/or surgery. Some individuals pursue exploratory tympanotomy, stapedotomy, placement of a total ossicular reconstruction prosthesis, cochlear implantation, insertion of a Wehr's prosthesis, decompression, and other surgical procedures. Widening of the external auditory canal is usually necessary to accommodate a hearing aid. Correction of hearing loss is difficult and only has limited success.
In forms of sclerosing bone dysplasias associated with short stature, most individuals make an effort to modify their environment to suit their height. For individuals who wish to treat their short stature, some progress in increasing height has been made by growth hormone (GH) supplementation in affected children. However, hormone supplementation can cause disproportionate growth, leading to longer arms and trunk and shorter legs.
Intracranial pressure is one of main features of sclerosing bone dysplasias, and the most severe. The increase in intracranial pressure caused by the increase in bone size and density often leads to headaches, hearing loss, blindness, facial paralysis, facial nerve palsies, and death. Accordingly, management of intracranial pressure includes monitoring for increased pressure, sudden onset of headaches, and blurred vision that may result in the need for decompression craniectomy or other forms of surgical decompression. Total decompression can prevent future attacks of facial paralysis in some forms of sclerosing bone dysplasias. Given the progressive nature of the sclerosing bone dysplasias, bone regrowth will occur and may cause recurrence of symptoms after surgery.
The abnormal formation of the head and skull bones impacts the form and function of the face, jaws, and remainder of the craniofacial skeleton. Surgery to correct bony overgrowth and density in the forehead, nose, and jaw bones is an option for some patients. Given the progressive nature of the sclerosing bone dysplasias, bone regrowth will occur and may cause recurrence of symptoms after surgery.
The objective of treatment for bone infection (osteomyelitis) in sclerosing bone dysplasias is to eliminate the infection and prevent the development of chronic infection. Intravenous antibiotics are started early and may later be changed, depending on culture results. Some new antibiotics can be very effective when given orally. In chronic infection, surgical removal of dead bone tissue is usually necessary.
Treatment of scoliosis depends upon the type of sclerosing bone dysplasias and the severity of the scoliosis. Treatment options may include observation, orthopedic braces, and surgery. In some cases, the progressive nature of the underlying condition makes correction of scoliosis difficult, if not impossible.
The treatment for clubfoot involves orthopedic surgery to correct the abnormal formation of the lower limbs. Correction of the abnormality may require multiple surgeries, and after care with casts, braces, and physical therapy.
Treatment of the myriad of dental issues associated with sclerosing bone dysplasias are managed best through comprehensive oral and dental care. A craniofacial team may be best suited to address the variety of issues. Mandible reduction is often performed for cosmetic reasons or if mouth closure is impaired as a result of overgrowth of the mandible. Tooth extraction may be difficult given the density of bone.
Individuals affected by sclerosing bone dysplasias may have pain from arthritis, neuralgia caused by pressure, dental pain, and other pain sources related to abnormal bone remodeling. Pain management for each of these sources is different. Severe pain resulting from nerve compression may be helped by nerve decompression surgery. Spinal cord decompression surgery may help alleviate back pain. A pain management specialist working with an individual's treatment team can determine the level of pain, determine the best medications to treat the pain, and evaluate the effectiveness of the medications.
Prognosis
The prognosis for individuals affected by sclerosing bone dysplasia varies greatly depending upon the type of sclerosing bone dysplasia and severity of symptoms. Individuals affected by delayed or adult-onset forms of sclerosing bone dysplasia may have mild to severe symptoms that do not reduce their lifespan. Individuals who present with symptoms at birth or soon after birth, like malignant infantile osteopetrosis and sclerosteosis, have a progressive course of disease that leads to early death. Increased intracranial pressure may result from a combination of circumstances and may have led, in several instances, to sudden death from impaction of the brainstem in the foramen magnum. Surgical procedures such as total decompression may increase length and quality of life.
BOOKS
De Villiers, J. C., and J. J. Du Plessis. "Neurosurgical Management of Sclerosteosis." In Operative Neurosurgical Techniques, edited by H.H. Scmidek, and W. H. Sweet. Philadelphia: W. B. Saunders Co., 1995.
PERIODICALS
Hamersma, H., J. Gardner, and P. Beighton. "The Natural History of Sclerosteosis." Clin Genet 63 (2003): 192–197.
Hofmeyr, L. M., and H. Hamersma. "Sclerosing Bone Dysplasias: Neurologic Assessment and Management." Curr Opin Otolaryngol Head Neck Surg 12, no. 5 (October 2004): 393–97.
