Clinical Features

The chief clinical characteristic of osteogenesis imperfecta is the extreme fragility and porosity of the bones, with an attendant proneness to fracture. The fractures heal readily, but the new bone is of a similar imperfect quality.

The age of onset of symptoms varies depending on the type of OI with fractures in type I and IV occurring during infancy and type II in utero. In type III, half the cases present fracture in utero, and other half in the neonatal period. No known differences based on gender exist. Prenatal screening by ultrasound during the second trimester shows bowing of long bones, fractures, limb shortening, and decreased skull echogenicity.

A second characteristic clinical feature of osteogenesis imperfecta is the occurrence of pale blue sclerae. The sclerae are abnormally thin, and for this reason the pigmented choroid shows through and produces the bluish color. However, the appearance of blue sclera is not confined to this disease since it may also be seen in osteopetrosis, fetal rickets, Turner syndrome, Paget’s disease, Marfan syndrome, and EhlersDanlos syndrome, as well as in normal infants. While the blue sclerae are a prominent sign in this disease, they are not invariably present. In a series of 42 patients reported by Bauze and his associates, 12 of the patients had white sclerae, and these were generally found in the older patients with the more severe disease and earlier onset of fractures.

In a thorough review of osteogenesis imperfecta and dentinogenesis imperfecta by Winter and Maiocco, the following additional signs and symptoms were described as being characteristic of osteogenesis imperfecta: deafness due to otosclerosis, abnormalities of the teeth (identical to those of dentinogenesis imperfecta, or ‘hereditary opalescent dentin’), laxity of the ligaments, a peculiar shape of the skull and an abnormal electrical reaction of the muscles.

Many patients with osteogenesis imperfecta also have a tendency towards capillary bleeding although no specific blood dyscrasia or defect has been demonstrated.

Physical features can vary depending on the type. It forms the basis for Sillence classification.

Oral Manifestations

Osteogenesis imperfecta is basically a disturbance of mesodermal tissues, particularly the calcified tissues. When a widespread congenital disturbance in bone formation exists, it is only logical to expect a concomitant disturbance in dentin formation. The large head size, frontal and temporal bossing, and exaggerated occiput create a greater percentage of class III malocclusions. Anterior and posterior cross bites and open bites are also frequent. These conditions seem to be caused by maxillary hypoplasia rather than mandibular hyperplasia. A surprising large number of impactions and ectopic teeth have been reported. In permanent dentition, OI patients often have unerupted first and second molars, a condition which is rare in the general population. These abnormalities have no relation to the existence of dentinogenesis imperfecta. Dentinogenesis imperfecta represents the disturbance in tooth formation associated with OI, and is one of the most significant clinical patterns of OI. It can be the only abnormality noted at times amongst the spectra of clinical manifestations. Therefore, clinical and radiological evaluations of the dentition may be the only affirmative component in the diagnosis of a questionable case of OI.

Radiographic Features

The radiographic hallmarks of osteogenesis imperfecta include osteopenia, bowing, angulation or deformity of the long bones, multiple fractures, and wormian bones (sutural bone) in the skull.

Histologic Findings

The bones in patients with osteogenesis imperfecta exhibit thin cortices, sometimes being composed of immature spongy bone, while the trabeculae of the cancellous bone are delicate and often show microfractures (Fig. 17-1). Osteoblastic activity appears retarded and imperfect, and for this reason the thickness of the long bones is deficient. The basic defect appears to lie in the organic matrix with failure of fetal collagen to be transformed into mature collagen. Qualitative defects (abnormal collagen I molecule) and quantitative defects (decrease in production of normal collagen I molecules) both exist. There is some evidence that the progressive intermolecular cross-linkage of adjacent collagen molecules, which is an essential characteristic of normal collagen maturation, is defective in this disease. Calcification proceeds normally. Defective microvascular system and decreased collagen fibril diameter have also been observed. The length of the long bones is usually normal unless multiple fractures have caused undue shortening.

Treatment and Prognosis

There is no known treatment for osteogenesis imperfecta. No medical therapy is involved, other than the treatment of infections when they occur. The prognosis varies from relatively good to very poor. In type IA, life expectancy is similar to that of general population; type II, most patients die within the first year of life. A slight decrease in life expectancy has been observed in the other types.

Clinical Features

The estimated incidence of Marfan syndrome ranges from 1 in 5,000 to 1 in 10,000 births which includes stillbirths. The wide variation in the sites of mutations noticed in the fibrillin gene causes the varied phenotypic manifestations of this syndrome. Several other diseases present similar to Marfan syndrome, making it exceedingly difficult to determine the exact incidence. The skeleton typically displays multiple deformities including arachnodactyly, dolichostenomelia (i.e. long limbs relative to trunk length), and thoracolumbar scoliosis. The shape of the skull and face is characteristically long and narrow, and commonly suggests the diagnosis of the disease (Figs. 17-2, 17-3). Other features of the disease include hyperextensibility of joints with habitual dislocations, kyphosis and flat feet. In the cardiovascular system, aortic dilation, aortic regurgitation, and aneurysms are the most worrisome clinical findings. Mitral valve prolapse requiring valve replacement can occur as well. Ocular findings include myopia, cataracts, retinal detachment, and superior dislocation of the lens.

Oral Manifestations

According to Baden and Spirgi, who have reviewed the oral manifestations of this disease, a high, arched palatal vault is very prevalent and may be a constant finding. Bifid uvula is also reported as well as malocclusion. In addition, multiple odontogenic cysts of the maxilla and mandible have occasionally been reported, most recently by Oatis and his coworkers. One additional finding sometimes present, is temporomandibular dysarthrosis (Fig. 17-4).

Radiographic Features

Skull radiographs (AP and lateral) may demonstrate a high arched palate, increased skull height, and an enlarged frontal sinus.

Treatment and Prognosis

There is no specific treatment for this condition. Recent strides in the management of the cardiovascular manifestations of Marfan syndrome have led to a significant decrease in morbidity and mortality. Patient longevity now approaches that of persons without Marfan syndrome, although cardiovascular compromise is still the most common cause of patient death.

Etiology

Type IA is an autosomal recessive disorder with an unknown chromosomal locus. Type IB is an autosomal recessive disorder resulting from mutations of the DDST (diastrophic dysplasia sulfate transporter) gene, which is located at 5q32– q33. Type II is an autosomal dominant type collagenopathy resulting from mutations in the COL2A1 (collagen 2 αl chain) gene, which is located at 12q13.1–q13.3. Different mutations in the gene encoding type II collagen (COL2A1) cause achondrogenesis type II as well as other type II collagenopathies (e.g. spondyloepiphyseal dysplasias, hypochondrogenesis).

Clinical Features

Achondrogenesis type I results in still-birth more frequently than type II. Males and females are affected equally. Achondrogenesis is detected prenatally or at birth because of typical clinical, radiographic, histological, and molecular findings.

In achondrogenesis type I, the craniofacial features include a disproportionately large head, soft skull, sloping forehead, convex facial plane, flat nasal bridge, occasionally associated with a deep horizontal groove, small nose, often with anteverted nostrils, long philtrum, retrognathia, increased distance between lower lip and lower edge of chin and double chin appearance (often). In achondrogenesis type II, the features seen are a disproportionately large head, large and prominent forehead, flat facial plane, flat nasal bridge, small nose with severely anteverted nostrils, normal philtrum (often), micrognathia (Fig. 17-5). The differential diagnoses include achondroplasia, hypophosphatasia, osteogenesis imperfecta and thanatophoric dysplasia.

Radiographic Features

The radiographic features may vary, and no single feature is consistently noticed. Distinction between type IA and type IB on radiographs is not always possible. Degree of ossification is age dependent, and caution is needed when comparing radiographs at different gestational ages.

Treatment and Prognosis

Medical care is supportive. No treatment is available for the underlying disorder. The condition is universally lethal.

Etiology

Patients with hypophosphatasia have defects in mineralization of bone due to TNSALP (tissue nonspecific alkaline phosphatase) deficiency. A mutation in the gene coding for tissue nonspecific alkaline phosphatase is believed to be the cause of hypophosphatasia. The gene, designated ALPL, is located at band 1p36.1–34.

Clinical Features

Hypophosphatasia affects all age groups; however, the severity of the disease differs with age. Males and females are affected equally. Hypophosphatasia occurs in all races. The perinatal form is considered lethal, while the infantile form has a mortality rate of 50%. Individuals with the other forms can reach adulthood, although often with increased morbidity. Patients with the childhood form often have rachitic deformities, and those with the adult type have increased morbidity from poorly healing stress fractures. All patients are affected by premature loss of dentition.

The perinatal form has the most severe manifestations. It is usually diagnosed at birth, and the infant rarely survives for more than a few hours. Death is due to respiratory failure. Marked hypocalcification of the skeletal structures is observed.

Patients with the infantile form may appear normal at birth; however, the clinical signs of hypophosphatasia appear during the first six months. This form also has respiratory complications due to rachitic deformities of the chest. Despite the presence of an open fontanelle, premature craniosynostosis is a common finding that may result in increased intracranial pressure. Hypercalcemia is also present and increased excretion of calcium may lead to renal damage.

Skeletal deformities, such as dolichocephalic skull and enlarged joints, a delay in walking, short stature, and a waddling gait accompany the childhood form. A history of fractures and bone pain usually exists as well. Premature loss of dentition is common with the incisor teeth often being the first affected.

The adult form presents during middle age. The first complaint may be foot pain, which is due to stress fractures of the metatarsals. Thigh pain, due to pseudofractures of the femur, may also be a presenting symptom. Upon obtaining an in-depth history, many of these patients will reveal that they had premature loss of deciduous teeth.

The only physical finding in the odontohypophosphatasic form is the premature loss of teeth.

Oral Manifestations

The earliest manifestation of the disease may be loosening and premature loss of deciduous teeth, chiefly the incisors. There are varying reports of gingivitis; however it does not seem to be a consistent feature of the disease. The differential diagnoses include achondrogenesis, osteogenesis imperfecta, rickets and thanatophoric dysplasia.

Radiographic Features

The childhood form is characterized by rachitic deformities. Upon radiologic examination of the metaphysis, evidence of radiolucent projections from the epiphyseal plate into the metaphysis is present. This is not found in other types of rickets. Radiographic findings are normal for patients with odontohypophosphatasia. Dental radiographs generally reveal hypocalcification of teeth and the presence of large pulp chambers, as well as alveolar bone loss; however these findings have not been consistently reported.

Histologic Findings

Histologic examination of the skeleton will reveal rachitic abnormalities of the growth plates such as failure of cartilage calcification. Both osteoclasts and osteoblasts appear morphologically normal, but the latter lack membrane associated alkaline phosphatase (ALP) activity on histochemical testing. This disrupts incorporation of calcium into the matrix. The long bones characteristically exhibit an increased width of proliferating cartilage with widening of the hypertrophic cell zone, irregularity of cell columns, irregular penetration of the cartilage by marrow with persistence of numerous cartilage islands in the marrow, and formation of large amounts of osteoid which is inadequately calcified. These findings are indistinguishable from those in true rickets. Histological examination of the teeth reveals a decrease in cementum, which varies with the severity of the disease. This is presumably as a result of failure of cementogenesis, so that there is no sound functional attachment of the tooth to bone by periodontal ligament. This lack of attachment is thought to account for the early spontaneous exfoliation of the deciduous teeth. The pulp chamber also appears to be enlarged. The incisors tend to be the most affected. Bone biopsy findings are normal for patients with odontohypophosphatasia.

Treatment and Prognosis

Currently, no medical therapy is available. Various treatments have been attempted including zinc, magnesium, cortisone, plasma, and enzyme replacement therapy. The results have been inconsistent. Orthopedic surgical involvement may be necessary in patients with hypophosphatasia. The perinatal form is considered lethal. The infantile form is thought to be fatal in approximately 50% of patients. Longevity studies have not been conducted for the infantile and childhood forms. Individuals with the adult and odontohypophosphatasia forms are believed to have normal lifespans.

Etiology

The primary underlying defect in all types of osteopetrosis is failure of the osteoclasts to resorb bone. This results in thickened sclerotic bones, which have poor mechanical properties. Increased bone fragility results from a failure of the collagen fibers to augment bone matrix and from defective remodeling of woven bone to compact bone. Heterogeneous molecular or genetic defects can result in impaired osteoclastic function. The exact molecular defects or sites of these mutations largely are unknown.

Clinical Features

Three distinct forms of the disease are based on age and clinical features. These are adult onset, infantile, and intermediate. Other rare forms have been described (e.g. lethal, transient, postinfectious). The infantile and intermediate types have an autosomal recessive mode of transmission, while the adult onset type shows autosomal dominant inheritance. If untreated, infantile osteopetrosis usually results in death by the first decade of life due to severe anemia, bleeding, or infection. Adult patients with osteopetrosis are usually asymptomatic and have good longterm survival rates.

Infantile osteopetrosis (also called malignant osteopetrosis) is diagnosed early in life. Failure to survive and growth retardation are symptoms. Bony defects occur. Nasal stuffiness due to mastoid and paranasal sinus malformation is often the presenting feature of infantile osteopetrosis. Cranial nerve entrapment neuropathies occur due to failure of the foramina in the skull to widen completely. Manifestations include deafness, proptosis, and hydrocephalus. Dentition might be delayed. Osteomyelitis of the mandible is common due to a deficient blood supply. Bones are fragile and can fracture easily. Defective osseous tissue tends to replace bone marrow, which can cause bone marrow failure with resultant pancytopenia. Patients might have anemia, easy bruising and bleeding (due to thrombocytopenia), and recurrent infections (due to inherent defects in the immune system). Extramedullary hematopoiesis might occur with resultant hepatosplenomegaly, hypersplenism, and hemolysis. Other manifestations include sleep apnea and blindness due to retinal degeneration.

Adult osteopetrosis (also called benign osteopetrosis) is diagnosed in late adolescence or adulthood. Approximately one half of the patients are asymptomatic, and the diagnosis is made incidentally (often in late adolescence because radiological abnormalities start appearing only in childhood) or is based on family history. Other patients might present with osteomyelitis or fractures. Many patients have bone pain. Bony defects are common and include cranial nerve entrapment neuropathies (e.g. with deafness, with facial palsy), carpal tunnel syndrome, and osteoarthritis. Bones are fragile and might fracture easily. Approximately 40% of patients have recurrent fractures. Osteomyelitis of the mandible occurs in 10% of patients. Bone marrow function is not compromised. Other manifestations include visual impairment due to retinal degeneration and psychomotor retardation. Physical findings are related to bony defects and include short stature, frontal bossing, a large head, nystagmus, hepatosplenomegaly, and genu valgum in infantile osteopetrosis. The differential diagnoses include hypoparathyroidism, myeloproliferative disease, Paget’s disease, pseudohypoparathyroidism and lead toxicity.

Oral Manifestations

The jaws are involved in the same manner as the other bones in the body, and the oral manifestations have been reviewed by Kaslick and Brustein. However, a clear distinction has usually not been made as to the type of the disease present, benign or malignant. The medullary spaces of the jaws are remarkably reduced in both dominant and recessive osteopetrosis so that there is a marked predilection for the development of osteomyelitis should infection gain entrance to the bone. This is a complication of dental extraction which has been reported frequently and discussed by Dyson. Similar findings were noted by Bjorvatn and his associates in four children with the malignant form of the disease. They stressed the necessity of administering large doses of antibiotics to control the recurring infection, which even then did not prevent the progressive osseous destruction. Fracture of the jaw during tooth extraction, even when the extraction is performed without undue force, may also occur because of the fragility of the bone. It has been reported that the teeth are of defective quality, enamel hypoplasia, microscopic dentinal defects and arrested root development all having been described. However, this may not be true in the benign dominant form of the disease. It is also reported that the teeth are especially prone to dental caries. Since dental findings have been recorded in so few cases, this observation is difficult to evaluate. An additional rather constant finding is retardation of tooth eruption due to the sclerosis of bone.

Radiographic Features

Radiographic features are usually diagnostic. Because the disease is a heterogeneous group of disorders, the findings vary depending on the subtype. Patients usually have generalized osteosclerosis. Bones may be uniformly sclerotic, but alternating sclerotic and lucent bands may be noted near the ends of long bones (Fig. 17-6). The bones might appear club like or show an appearance of a bone within bone (endobone). The entire skull is thickened and dense, especially at the base. Sinuses are small and underpneumatized. Vertebrae are extremely radiodense. They may show alternating bands, known as the ‘rugger-jersey’ sign. Radiographs may show evidence of fractures or osteomyelitis. When the jaws are affected, the density of the bone may be such that the roots of the teeth are nearly invisible on the dental radiograph.

Laboratory Findings

The patients manifest a myelophthisic anemia due to the displacement of hematopoietic marrow tissue by bone. Hypocalcemia can occur and cause rickets if it is severe enough. Parathyroid hormone (PTH) is often elevated (secondary hyperparathyroidism). Acid phosphatase and creatinine kinase (CK-BB) levels are increased due to increased release from defective osteoclasts.

Histologic Features

Bone biopsy is not essential for diagnosis because radiographs are usually diagnostic. Osteopetrosis is characterized by the endosteal production of bone with an apparent concomitant lack of physiologic bone resorption (Fig. 17-7). Osteoblasts are prominent, but osteoclasts are seldom found in significant numbers in tissue sections. The predominance of bone formation over resorption typically leads to the persistence of cartilaginous cores of bony trabeculae long after their replacement should have occurred in endochondral bones. The trabeculae themselves are disorderly in arrangement, and the marrow tissue present is usually fibrous.

It has been reported by Johnston and his associates; however, that adult patients with benign osteopetrosis do not appear to have a deficiency in osteoclastic activity but rather an abnormality in the type and structure of bone. They found osteoblastic and osteoclastic activity with prominent remodeling of bone. However, by polarized light, the bone was found to be markedly deficient in collagen matrix fibrils and these seldom crossed from one osteon to another. This deficiency of fibrils could account for the tendency for fracture in these patients.

Treatment and Prognosis

Infantile osteopetrosis warrants treatment due to the adverse outcome associated with the disease. Calcitriol appears to help by stimulating dormant osteoclasts, and thus, stimulating bone resorption. Erythropoietin can be used to correct anemia. Corticosteroids have been used with the hope of stimulating bone resorption and treating the anemia. Treatment with gamma interferon has been shown to produce long-term benefits. Adult osteopetrosis requires no treatment by itself, though complications of the disease might require intervention. No specific medical treatment exists for the adult type. If untreated, infantile osteopetrosis usually results in death by the first decade of life due to severe anemia, bleeding, or infections. Patients fail to survive, have growth retardation, and increased morbidity. Prognosis can change remarkably in some patients after bone marrow transplantation. Patients with adult osteopetrosis have good long-term survival rates.