Ocular Manifestations of Osteopetrosis
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Disease Entity
Disease
Osteopetrosis is a rare, metabolic disease characterized by abnormal growth of bones that become overly dense and diffusely sclerotic, predisposing to fractures. Osteopetrosis is typically an inherited disorder that is passed from one or both parents to a child.
Epidemiology
The prevalence of Osteopetrosis largely depends on the subtype. Autosomal dominant osteopetrosis, the most common subtype, has an estimated incidence of 1 out of every 20,000 newborns1. The autosomal recessive subtype, commonly called “malignant osteopetrosis” is much rarer, occurring in 1 out of every 250,000 births, with some studies reporting a notable higher incidence in Costa Rica.2
Ocular Manifestations
Progressive Vision Loss/Blindness
Excessive growth of bony tissue may cause compression of the optic canals with secondary compressive optic neuropathy, progressive visual loss, and in some cases blindness3.
Cranial Nerve Palsies
The pathophysiology of the various cranial nerve palsies seen in osteopetrosis stems from foramina narrowing due to bony growths, particularly cranial nerves III, IV, and VI within the superior orbital fissure. Facial nerve palsies presenting as lagophthalmos have also been reported in children with osteopetrosis3.
Venous Outflow Obstruction
Venous outflow obstruction can occur, resulting in neuro-ophthalmic consequences such as cerebrospinal fluid accumulation and papilledema seen on ophthalmoscopy.
Additional Ocular Symptoms Reported
Visual symptoms seen with this disease include widely spaced eyes, exophthalmos, strabismus, and involuntary rhythmic eye movements (nystagmus). Additionally, cases of retinal atrophy have been reported.
Genetics
There are three main subtypes of osteopetrosis which are classified based on their mode of inheritance: autosomal dominant, autosomal recessive, and X-Linked recessive. The age of symptom onset and severity of the disease course are largely determined by the inheritance pattern. Currently, 23 genes have been identified that contribute to the development of osteopetrosis4
Genetic Subtypes:
1) Autosomal dominant osteopetrosis (also known as Albers-Schonberg disease) is the most common form. Those with this type of osteopetrosis develop symptoms after infancy and can have a wide range of symptom severity, even among direct family members. Many times, those with this type of Osteopetrosis are not diagnosed until adolescence or early adulthood and generally have a milder disease course.
2) Autosomal recessive osteopetrosis is the more severe form of the disorder. Those with this form present with symptoms shortly after birth) and usually have a shortened life expectancy. Someone with autosomal recessive osteopetrosis may have parents who show no signs of the disease.
3) X- linked osteopetrosis is the rarest type of the disease. This form of osteopetrosis usually affects boys.
Pathophysiology
The pathophysiology of osteopetrosis is characterized by diffuse sclerotic thickening of bones caused by a defect in osteoclasts. Regardless of the genetic inheritance pattern of the disease, all types of osteopetrosis result from a defect in osteoclast formation and/or function. Osteoclasts are highly specialized cells that normally function to resorb bone during remodeling, maintaining the crucial balance seen in skeletal bone homeostasis which utilizes both osteoclast and osteoblast cells5. When osteoclasts do not function properly, bone is not resorbed, resulting in the accumulation of defective bony architecture. Brittle and overly dense bones result, which are particularly susceptible to fracture and/or skeletal abnormalities. More recently, the role of osteoblast cells in the pathophysiology of osteopetrosis has also been demonstrated. This is hypothesized to either be due to intrinsic defects within osteoblasts or enhanced osteoblast activity due to osteoclast down regulation and resulting lack of inhibition6.
Diagnosis
History
Osteopetrosis was first described by the German radiologist Dr. Albers-Schonberg in 1904.7 Originally referred to as “marble bone disease”, it acquired the name Osteopetrosis in 1926 after radiographs demonstrated opaque bones with a porous cortex, more closely resembling limestone than marble8.
Systemic Manifestations
The most common manifestations of osteopetrosis include bone fractures, visual and hearing changes due to cranial nerve compression, and nasal congestion resulting from narrowing of the sinus cavities. Additionally, osteomyelitis and pancytopenia (notably anemia) caused by bone marrow failure have been reported in osteopetrosis patients. Many patients also suffer from malformed teeth or a delay in tooth eruption, causing significant pain and increased infection risk.
Radiographic Features
Osteosclerosis, particularly of the calvarium, can be identified on standard X-rays and is highly suggestive of osteopetrosis. So called “endobones” are also commonly noted on radiographs of the spine or hand phalanges, which have been described as having a “bone within a bone” appearance9. DEXA (dual energy X-ray absorptiometry) scans are another tool used to quantify the degree of osteopetrosis, with even the mildest forms of osteopetrosis causing a significant increase on Z-scores, sometimes greater than or equal to 5 standard deviations10. CT has been used to monitor the diameter of the optic canals in these patients to quantify the degree of nerve compression11.
Treatment
Patients with osteopetrosis require consistent and timely ophthalmic monitoring, as well as a multidisciplinary healthcare team to address their medical needs. Currently, bone marrow transplant is the only curative treatment, and is reserved for the autosomal recessive type of osteopetrosis12. Bone marrow transplant has been suggested as an infantile osteopetrosis intervention with the potential to preserve or restore vision13,14. Other treatments focus on symptomatic relief, such as optic nerve decompression surgery. Case reports have shown the halting of vision deterioration with early decompression of the optic canals as an intervention, particularly in those with malignant osteopetrosis15, 16.
References
1. Bollerslev J, Andersen PE. Radiological, biochemical and hereditary evidence of two types of autosomal dominant osteopetrosis. Bone. 1988;9(1):7-13. doi:10.1016/8756-3282(88)90021-x
2. Loría-Cortés R, Quesada-Calvo E, Cordero-Chaverri C. Osteopetrosis in children. The Journal of Pediatrics. 1977;91(1):43-47. doi:10.1016/s0022-3476(77)80441-1
3. Loke JY, Mohd Ali H, Kamalden TA. Osteopetrosis craniopathy: A rare cause of bilateral compressive optic neuropathy and facial nerve palsy. Postgraduate Medical Journal. 2019;95(1127):513-513. doi:10.1136/postgradmedj-2019-136527
4. Nadyrshina DD, Khusainova RI. Clinical, genetic aspects and molecular pathogenesis of osteopetrosis. Vavilov Journal of Genetics and Breeding. 2023;27(4):383-392. doi:10.18699/vjgb-23-46
5. Takegahara N, Kim H, Choi Y. Unraveling the intricacies of osteoclast differentiation and maturation: Insight into novel therapeutic strategies for bone-destructive diseases. Experimental & Molecular Medicine. 2024;56(2):264-272. doi:10.1038/s12276-024-01157-7
6. Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis. Bone. 2008;42(1):19-29. doi:10.1016/j.bone.2007.08.029
7. Stark Z, Savarirayan R. Osteopetrosis. Orphanet Journal of Rare Diseases. 2009;4(1). doi:10.1186/1750-1172-4-5
8. Whyte MP. Osteopetrosis: Discovery and early history of “Marble bone disease.” Bone. 2023;171:116737. doi:10.1016/j.bone.2023.116737
9. Curé JK, Key LL, Goltra DD, VanTassel P. Cranial MR imaging of osteopetrosis. American Journal of Neuroradiology. June 1, 2000. Accessed August 28, 2024. https://www.ajnr.org/content/21/6/1110.
10. Ladd LM, Imel EA, Niziolek PJ, et al. Radiographic imaging, densitometry and disease severity in autosomal dominant osteopetrosis type 2. Skeletal Radiology. 2020;50(5):903-913. doi:10.1007/s00256-020-03625-3
11. Maximova N, Zennaro F, Gregori M, Boz G, Zanon D, Mbalaviele G. Hematopoietic stem cell transplantation-induced bone remodeling in autosomal recessive osteopetrosis: Interaction between skeleton and hematopoietic and sensory nervous systems. Bone. 2020;130:115144. doi:10.1016/j.bone.2019.115144
12. Gerritsen EJA, Vossen JM, Fasth A, et al. Bone marrow transplantation for autosomal recessive osteopetrosis a report from the Working Party on Inborn Errors of the European Bone Marrow Transplantation Group. The Journal of Pediatrics. 1994;125(6):896-902. doi:10.1016/s0022-3476(05)82004-9
13. Kerr NC, Wang WC, Mohadjer Y, Haik BG, Kaste SC, Horwitz EM. Reversal of optic canal stenosis in osteopetrosis after bone marrow transplant. American Journal of Ophthalmology. 2000;130(3):370-372. doi:10.1016/s0002-9394(00)00543-2
14. Cao W, Wei W, Yu G, Wu Q, Qin M. Comparison of optic canal diameter in children with malignant infantile osteopetrosis and normal children and the effects of hematopoietic stem cell transplantation on the optic canal diameter. Journal of Pediatric Ophthalmology & Strabismus. 2019;56(1):35-42. doi:10.3928/01913913-20180921-01
