Osteopetrosis

Adult-onset osteopetrosis
X-ray of the pelvis of a patient with osteopetrosis, adult onset form (Albers-Schönberg disease). Note the dense appearance
Classification and external resources
Specialty	medical genetics
ICD-10	Q78.2
ICD-9-CM	756.52
OMIM	166600 259700
DiseasesDB	9377
eMedicine	med/1692
Patient UK	Osteopetrosis
MeSH	D010022

Osteopetrosis, literally "stone bone", also known as marble bone disease, is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle, or osteomalacia, in which the bones soften. Osteopetrosis can cause bones to dissolve and break.^[1]

It is one of the hereditary causes of osteosclerosis.^[2] It is considered to be prototype of osteosclerosing dysplasias. The cause of the disease is understood to be malfunctioning osteoclasts. Radiological findings will show a bone-in-bone appearance.^[3]

Signs and symptoms

A 17-year-old male with osteopetrosis: Typical cranial deformity and thoracic scoliosis

Despite this excess bone formation, people with osteopetrosis tend to have bones that are more brittle than normal. Mild osteopetrosis may cause no symptoms, and present no problems. However, serious forms can result in stunted growth, deformity, and increased likelihood of fractures; also, patients suffer anemia, recurrent infections, and hepatosplenomegaly due to bone expansion leading to bone marrow narrowing and extramedullary hematopoiesis. It can also result in blindness, facial paralysis, and deafness, due to the increased pressure put on the nerves by the extra bone.^[4]

Malignant infantile osteopetrosis

Malignant infantile osteopetrosis or (Infantile autosomal recessive osteopetrosis) is a rare type of skeletal dysplasia characterized by a distinct radiographic pattern of overall increased density of the bones with fundamental involvement of the medullary portion. Infantile osteopetrosis typically manifests in infancy. Diagnosis is principally based on clinical and radiographic evaluation, confirmed by gene analysis where applicable.^[5] As a result of medullary canal obliteration and bony expansion, grave pancytopenia, cranial nerve compression, and pathologic fractures may ensue. The prognosis is poor if untreated. The classic radiographic features include, endobone or “bone-within-bone” appearance in the spine, pelvis and proximal femora, upper limbs and short tubular bones of the hand. Additionally, there is the Erlenmeyer flask deformity type 2 which is characterized by absence of normal diaphyseal metaphyseal modelling of the distal femora with abnormal radiographic appearance of trabecular bone and alternating radiolucent metaphyseal bands.^[5] The precise and early diagnosis of infantile osteopetrosis is important for management of complications, genetic counselling and timely institution of appropriate treatment namely hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation offers a satisfactory treatment modality for a considerable percentage of infantile osteopetrosis.^[6] Amelioration of radiographic bone lesions after hematopoietic stem cell transplantation in infantile osteopetrosis have been proposed to be important indicators of success of hematopoietic stem cell transplantation. Few publications with limited study participants have demonstrated the resolution of skeletal radiographic pathology following hematopoietic stem cell transplantation.^[7][8]

Pathogenesis

Normal bone growth is achieved by a balance between bone formation by osteoblasts and bone resorption (breakdown of bone matrix) by osteoclasts.^[9] In osteopetrosis, the number of osteoclasts may be reduced, normal, or increased. Most importantly, osteoclast dysfunction mediates the pathogenesis of this disease.^[10]

Osteopetrosis is caused by underlying mutations that interfere with the acidification of the osteoclast resorption pit, for example due to a deficiency of the carbonic anhydrase enzyme encoded by the CA2 gene.^[11] Carbonic anhydrase is required by osteoclasts for proton production. Without this enzyme hydrogen ion pumping is inhibited and bone resorption by osteoclasts is defective, as an acidic environment is needed to dissociate calcium hydroxyapatite from the bone matrix. As bone resorption fails while bone formation continues, excessive bone is formed.^[12]

Variations

Protein TNFSF 11(RANKL)

Diagnosis

Diagnosis is largely based upon an accurate correlation between the clinical and radiologic data and molecular analysis where available.

Differential diagnosis

The differential diagnosis of osteopetrosis includes other disorders that produce osteosclerosis. They constitute a wide array of disorders with clinically and radiologically diverse manifestations. Among the differential diagnosis are hereditary ostoesclerosing dysplasias such as; neuropathic infantile osteopetrosis, infantile osteopetrosis with renal tubular acidosis, infantile osteopetrosis with immunodeficiency, infantile osteopetrosis with leukocyte adhesion deficiency syndrome (LAD-III), pyknodysostosis (osteopetrosis acro-osteolytica), osteopoikilosis (Buschke–Ollendorff syndrome), osteopathia striata with cranial sclerosis, mixed sclerosing skeletal dysplasias, progressive diaphyseal dysplasia (Camurati–Engelmann disease), SOST-related sclerosing skeletal dysplasias.^[5] Besides, the differential diagnosis includes acquired conditions that induce osteosclerosis such as osteosclerotic metastasis notably carcinomas of the prostate gland and breast, Paget's disease of bone, myelofibrosis (primary disorder or secondary to intoxication or malignancy), Erdheim-Chester disease, osteosclerosing types of osteomyelitis, sickle cell disease, hypervitaminosis D and hypoparathyroidism.^[13]

Treatment

The only treatment that offers long-term survival rates and amelioration of hematologic and skeletal manifestations is hematopoietic stem cell transplantation. This is especially true to malignant infantile osteopetrosis.^[7][8][14] If complications occur in children, patients can be treated with vitamin D. Gamma interferon has also been shown to be effective, and it can be associated to vitamin D. Erythropoetin has been used to treat any associated anemia. Corticosteroids may alleviate both the anemia and stimulate bone resorption. Fractures and osteomyelitis can be treated as usual.

Prevalence

Worldwide, there is 1 affected newborn out of every 20,000 to 250,000,^[15] but the odds are greater in the Russian region of Mari El (1 of every 14,000 newborns) and much greater in Chuvashia (1 of every 3,500—4,000 newborns) due to genetic features of the Mari people and Chuvash people, respectively.^[16][17]

Notable cases

• Laurel Burch^[18]
• Lil Bub

References

Further reading

• GeneReviews/NCBI/NIH/UW entry on CLCN7-Related Osteopetrosis