When bone becomes marble: Head and neck manifestations of osteopetrosis

Abstract

Osteopetrosis is a genetically determined bone disease resulting from malfunction of osteoclastic activity, leading to excessive deposition of immature bone. This may result in complete agenesis of the paranasal sinuses, oral complications and multiple cranial neuropathies. The case of a 12-year-old boy with osteopetrosis is presented.

Osteopetrosis, or marble bone disease, was initially reported by Albers-Schönberg in 1904 as delayed physical development accompanied by bone fragility (1). It is a pathologically descriptive term referring to a variety of clinical diseases (2). In humans, the spectrum ranges from mild medical illnesses to severe, lethal conditions. It is genetically determined as either an autosomal dominant benign type or an autosomal recessive malignant type. An intermediate type described by Beighton et al (3) is more prevalent in practice. In the recessive form, the child is severely symptomatic early in life and usually dies of complications of the disease, mainly infections. The dominant type, on the other hand, which is also known as osteopetrosis tarda, is more compatible with life. Tips and Lynch (4) reported no racial or sexual predisposition. A defect in the mechanism of bone remodelling exists and leads to a series of somatic problems in the affected person. Malfunction of osteoclastic activity results in excessive formation of immature bone, thickening of the cortical bones, and narrowing or obliteration of the medullary cavities. It is believed that osteoclasts fail to release the necessary lysosomal enzymes for bone resorption into the extracellular space (5,6). Defects in different genes have been described that lead to a phenotype with osteopetrosis. These defects include mutations in the gene encoding carbonic anhydrase II, the proton pump gene and the chloride channel gene. Recently, the immune response has been incriminated in the pathogenesis of various metabolic bone diseases, including osteopetrosis. Both cytotoxic T lymphocyte-associated antigen 4 and programmed death-1, a newly identified immunoregulatory receptor, have been shown to negatively regulate immune responses, and to affect osteoclastogenesis and bone remodelling (7). The clinical presentation and radiological picture may vary according to the severity of the disease (Table 1). Bone marrow transplantation has been shown to restore this osteoclastic activity and to alleviate symptoms (8).

TABLE 1.

Pathophysiology and clinicoradiological findings of patients with osteopetrosis

Pathophysiology	Clinical manifestation	Radiographic finding
Osteoclast malfunction secondary to:	Renal tubular acidosis	Diffuse increase in bone density
Gene function defects	Developmental delay	Metaphyseal widening
Carbonic anhydrase II deficiency	Short stature	Absence of bone marrow cavity
Osteoclast proton pump deficiency	Cranial nerve dysfunction	Increased density of skull base
Defects in chloride channel	Visual impairment	‘Endobone’ formation of pelvis and vertebral end plates
Other unknown causes	Frontal bossing
Alteration in immune response	Hepatosplenomegaly
Cytotoxic T lymphocyte-associated antigen 4	Hypocalcemia
Programmed death-1 receptor	Frequent fractures

In the present paper, we will review the pathogenesis and clinical picture of this rare entity in the context of a case report.

CASE PRESENTATION

A 12-year-old boy (height 137 cm, weight 31 kg – well below the third percentile for age and sex) with known osteopetrosis was admitted for the management of a right subtrochanteric fracture. He was first diagnosed at the age of three months when, on investigation of his anemia and hepatosplenomegaly, he was found to have high cranial indices on skull x-ray with evidence of increased bone density and thickening at the base of the skull. A skeletal survey was done and a diagnosis of Albers-Schönberg disease was made. The family history was positive for a brother diagnosed with osteopetrosis, who died at an early age (younger than one year). At five years of age, the patient had an intertrochanteric fracture of the right hip and fracture of the right radius and ulna. At 10 years of age, he had a right subtrochanteric fracture, followed two years later by a right femur and intertrochanteric fracture.

We were consulted for the management of right facial swelling and redness. The swelling had progressed over three weeks before admission, with right gingival pain and occasional bleeding. There was no fever, purulent nasal discharge or symptoms suggestive of sinusitis. There was no history of facial paresis, visual disturbances, sensory changes or noticeable decrease in hearing. On physical examination, he had swelling, tenderness and erythema of the right mid-third of the face, with purulent discharge in the gingivolabial sulcus at the level of the first molar. A swab taken of the discharge grew normal flora. The ear examination revealed bilateral dull tympanic membranes. The head and neck examination was normal. There was no evidence of optic nerve or other cranial nerve involvement. A panoramic view of the lower jaw showed many unerupted teeth, with no evidence of apical or periapical abscesses. Computed tomography of the facial bones showed a significant increase in the density of the visualized bones compatible with the clinical diagnosis of osteopetrosis. There was no aeration of the paranasal sinuses (Figure 1). There was evidence of infiltration of the subcutaneous soft tissues of the right cheek along the right side of the upper alveolar ridge, with enlargement of the right mastication muscles. No signs of bone erosion or abscess formation were present. There was also poor aeration of the mastoid air cells, with no evidence of internal auditory canal narrowing (Figure 2). An audiogram at that time showed mild bilateral conductive hearing loss, with an air-bone gap ranging between 0 db and 20 db; a type B tympanogram and absent bilateral reflexes were also noted. The diagnosis was a right gingivobuccal draining fistula because of the persistent discharge. The patient was started on a broad-spectrum antibiotic with the presumed diagnosis of an infection. Failure to respond necessitated debridement of the right buccogingival draining fistula. The submitted fragments of bone showed extensive necrosis, with replacement of the bone marrow spaces by sheets of plasma cells and lymphocytes. Microscopic examination of the soft tissues retrieved showed signs of chronic inflammation. The pathological diagnosis was consistent with osteomyelitis. Repeated cultures from the infected specimen grew Streptococcus viridans sensitive to all antibiotics. The patient was kept on broad-spectrum antibiotics for a few weeks, but his symptoms persisted. He underwent further debridement of the gingiva and maxillary bone twice within the following year. The pathological diagnosis was again consistent with chronic inflammation and osteomyelitis. Following the aggressive surgical intervention and the prolonged course of antibiotics, the patient improved. He was then followed up for his otitis media with effusion, with the possibility of insertion of pressure-equalizing tubes. The effusion resolved after six months and the hearing improved. The patient is currently doing well. He is still prepubertal at 15 years of age and shows delayed growth. His stature is below the third percentile and his weight is at the fifth percentile for his age. His anemia improved after a splenectomy was performed two years ago. He still has an enlarged liver and his last hemoglobin was 10 g/dL. He was initially considered for bone marrow transplantation, but his condition is currently stable.

Figure 1).

Computed tomographic scan with coronal cut of the paranasal sinuses showing agenesis of the maxillary (arrow) and ethmoidal air cells

Figure 2).

Computed tomographic scan of the temporal bones showing poor aeration of the mastoid air cells (arrow)

DISCUSSION

The present case report shows the potential severity of facial bone and sinus involvement in osteopetrosis when systemic disease is relatively mild. Despite the stability of his general condition, our patient has suffered chronic osteomyelitis of the maxilla, which has necessitated repeated surgical interventions.

The clinical manifestations of osteopetrosis vary in severity and time of onset. The malignant form presents with devastating symptoms early in childhood and rapid worsening of the condition, resulting in a short lifespan, whereas the benign form may be diagnosed late in childhood with a variety of prominent clinical features, such as frontal bossing, leonine facies, malocclusion of teeth and hepatosplenomegaly (9). Atypical features may include microcephaly and a normal upper segment to lower segment ratio. A radiological skeletal survey usually reveals increased bone density with poor differentiation between the cortex and the medulla.

The defective remodelling process characteristic of osteopetrosis has many clinical implications in the head and face regions, the core of the present case report. Cranial imaging of autosomal recessive osteopetrosis shows small optic canals, orbits and nasoethmoid complex. The paranasal sinuses are either poorly pneumatized, like the mastoid air cells, or show bud formation (10). Areas of condylar cartilage calcification may be seen (11). These radiological characteristics of underdevelopment may support the theory that delayed maturation is the primary morphological abnormality in osteopetrosis and that bone thickening is a secondary manifestation to reduced bone turnover. Of importance in the head and neck region is the stenosis and compression of the cranial foramina, resulting in multiple cranial palsies. The optic, olfactory, trigeminal, facial and cochlear nerves are most commonly affected. Cummings et al (12) reported the case of a six-month-old infant who was diagnosed with malignant autosomal recessive osteopetrosis and was found to have optic nerve pallor secondary to orbital fissure narrowing (seen on computed tomography of the brain).

Deafness is the most common presenting symptom of temporal bone involvement. Unlike blindness, which is primarily due to optic canal stenosis, deafness is conductive rather than sensorineural. The hypothesis that hearing loss is primarily due to internal auditory canal stenosis secondary to bony overgrowth does not always hold true (13). The conductive hearing loss has been attributed to exostosis projecting into the middle ear cavity, calcified and sclerotic ossicles, and recurrent otitis media (14–17). Ear infections can also be due to compromised mucociliary clearance and thickening mucosa lining the eustachian tube, with the presence of microscopic mucus inclusion cycts as decribed by Blum and Hines (13) and Hawke et al (17). Our patient had a conductive hearing loss secondary to bilateral otitis media with effusion.

Other histological features of the temporal bone described in patients with osteopetrosis include the presence of a fetal (ring-like) shape of the stapes and persistence of the stapedial artery, as described by Myers and Stool (18). An intermediate primitive form of the stapes between the ring shape of the fetus and the adult appearance has also been reported (6). Variations in the histological characteristics of the otic capsule ranging from a normal endochondral layer to abnormal blue staining have also been described (18). Milroy and Michaels (15) reported thickening of all three layers of the otic capsule with an increase in the interossei globuli.

Vestibular symptoms have rarely been described in comparison with the cochlear symptoms, and this has been attributed to the presence of normal vestibular structures on histological examination (9,17).

Facial nerve palsies have been reported by several authors, including Hamersma (19), Yarington and Sprinkle (20), and Wong et al (21). Even though facial nerve palsies have been ascribed to bony overgrowth of the facial canal with resultant facial nerve compression, histological examination often failed to substantiate this correlation and instead showed dehiscence of the facial canal with herniation of the nerve into the middle ear cavity (22). Another explanation for the recurrent facial palsy may be that the acute otitis media affects the dehiscent nerve (17). Trigeminal nerve involvement has also been described and related to bony overgrowth, leading to weakness in the muscles of mastication and sensory changes along the distribution of the nerve (23).

Hydrocephalus with an increase in cerebrospinal fluid pressure due to impairment of venous drainage may present as headache in patients with osteopetrosis.

The oral aspects of osteopetrosis became more salient with the increase in the lifespan of these patients. Bjorvatn et al (24) reported great distortion in the primary molars and permanent teeth of children with malignant osteopetrosis. There was a limitation of the vertical growth of the alveolar ridge, with embedding of the teeth into the basal bone. Any injury or fenestration in the overlying oral mucosa may lead to osteitis and extraoral fistula formation. Bjorvatn et al (24) described the odontogenic features of patients with osteopetrosis as enamel hypoplasia, dentinal defects and delayed teeth eruption. Batra and Shah (25) reported a case of osteomyelitis of the mandible following tooth extraction in a 19-year-old woman with malignant osteopetrosis. This result was attributed to the poor bone vascularization and reduced local defences. In the present case, the patient had soft tissue swelling and infiltration of the right cheek. Most teeth were unerupted and the paranasal sinuses were not aerated (as seen on computed tomographic evaluation of the facial bones). The initial clinical diagnosis was a draining gingivobuccal fistula; however, failure to respond to broad-spectrum antibiotics and the pathological description of the debrided bony fragments of the right maxilla shifted the diagnosis to chronic osteomyelitis. The etiology behind it was most likely the unerupted teeth of the upper jaw. The chronicity of this infection has necessitated repeated surgical intervention for further debridement of the necrotic tissues and infected bone. Early diagnosis of osteomyelitis in patients with draining fistulas in the oral cavity and aggressive surgical intervention are extremely important issues in the management of these conditions.

Table 2 summarizes the head and neck manifestations of osteopetrosis.

TABLE 2.

Head and neck manifestations of osteopetrosis

Sign or symptom	Radiological or histological finding
Headache	Hydrocephalus, impairment of cranial nerve drainage
Leonine facies, frontal bossing, hypertelorism	Defective remodelling process, thickening of bone
	Small orbits
	Abnormal nasoethmoid complexes
Visual disturbances	Narrowing of the optic canal
Anosmia	Thickening of bone at cribriform plate
Facial paresis or paralysis	Overgrowth of facial canal
	Herniation of facial nerve
	Recurrent otitis media
Facial sensory changes	Overgrowth of bone at cranium resulting in compression of multiple branches of the trigeminal nerve
Vertigo (rare)	Normal vestibular structures
Conductive hearing loss	Otitis media with effusion
	Narrowed eustachian tube
	Ossicular joint ankylosis
	Persistence of fetal stapes (ring-like)
	Exostosis in the middle ear
Sensory neural hearing loss	Narrowing in internal auditory canal
	Thickening of the optic capsule layers
Sinuses	Poor pneumatization of sinuses, bud formation
	Complete agenesis
Malocclusion	Distortion in primary molars and permanent teeth
	Condylar cartilage calcification
Odontogenic features	Enamel hypoplasia
	Dentinal defects
	Delayed teeth eruption
Soft tissue swelling	Osteitis of upper or lower jaw
	Oral fistula
	Abscess and subcutaneous tissue infiltration

CONCLUSION

Osteopetrosis is a metabolic disease of bone with a devastating clinical picture. The defect in bone formation and resorption due to osteoclastic malfunction results in an increase in bony mass. Long bones lose their hard structure to withstand stress, and narrowing of the cranial foramina results in neurological symptoms. The otolaryngological and systemic manifestations of this disease are too broad to enumerate. Deafness and the oral aspects of osteopetrosis, such as infections and odontogenic disease, are what prompted our involvement with the affected child, and treatment can be very unsatisfactory unless early intervention occurs.