Delhi Journal of Ophthalmology

Primary Optic Atrophy in Osteopetrosis

*Chintan Dedhia, Nilesh Parekh, Neepa Gohil, Hetal Patel, Yogesh Parmar
Department of Ophthalmology,
Government Medical College & Sir Takhtsinhji Hospital,
Bhavnagar, Gujarat, India.

Corresponding Author:

Chintan Dedhia
Department Of Ophthalmology,
Room no. 135, First floor,
New OPD building,
Sir Takhtsinhji hospital,
Jail road,
Bhavnagar -364001, Gujarat, India
Email - drchintand@gmail.com


Published Online: 25-SEP-2013

DOI:http://dx.doi.org/10.7869/djo.2013.26

Abstract
Osteopetrosis is a rare disorder of defective osteoclastic resorption of  bone, resulting in abnormally dense bones. Two main forms are milder adult onset autosomal dominant form and severe infantile malignant autosomal recessive form. Both types of mutations lead to disturbances of acidification  needed for normal osteoclast function. We report a rare ocular finding in a rare case of malignant variety of osteopetrosis. A five month old girl child diagnosed as malignant variety of osteopetrosis with failure to thrive on fundus examination revealed chalky white optic discs with sharply demarcated borders bilaterally. Cranial neuropathies are caused due to improper bone remodeling leading to narrowing of cranial nerve foramina and compression of nerves in skull foramina. Allogeneic hematopoietic stem cell transplantation is the only treatment known to significantly alter the course of disease.

Keywords :Optic Atrophy • osteopetrosis • bone-in-bone • bone marrow transplant • osteoclasts

Osteopetrosis also known as Osteitis Condensans Generalisata, Marble Bone disease, Albers Schonberg disease is a rare disorder of defective osteoclastic resorption of bone, resulting in abnormally dense bones. Two main forms are milder adult onset autosomal dominant form and severe infantile malignant autosomal recessive form. Both forms are due to mutations leading to disturbances of acidification needed for normal osteoclast function. We report a rare ocular finding of primary optic atrophy in a rare case of malignant variety of osteopetrosis.

A five month old girl child born of primary consanguinity, third by birth order, presented with excessive crying, difficulty in taking feeds, breathlessness and recurrent episodes of infections since birth. Gestational and family history was insignificant with other siblings being normal. Examination revealed pallor, puffiness of face, reduced weight and height, Protein Energy Malnutrition Grade 3, respiratory distress, hepatosplenomegaly, dental caries, absent neck holding and psychomotor delay.Investigations showed anaemia, severe thrombocytopenia, deafness (on BERA), markedly raised alkaline phosphatase, hypophosphatemia and hypovitaminosis D. Radiologically, X-rays of spine,skull,thorax,forearm,hand,pelvis,thigh (Figure 1) show dense homogeneous appearance with characteristic bone-in-bone appearance. On ocular examination, patient was not following light, Doll’s eye movement was absent, pupils non-reactive to light directly or consensually, rest anterior segment examination was unremarkable in both eyes. Fundus examination (Figure 2a, 2b) revealed chalky white optic discs with well defined margins without any gliosis or disc edema bilaterally. This case was diagnosed as malignant variety of osteopetrosis with failure to thrive with primary optic atrophy. The patient was admitted and treated symptomatically while monitoring vitals. Patient was discharged with the advice of exclusive breast feeding, following vaccination schedule, avoiding trauma and was advised for bone marrow biopsy for consideration of bone marrow transplant(BMT). But two weeks later, patient succumbed to her systemic condition.

Discussion

Two main forms of osteopetrosis are milder adult onset autosomal dominant form due to mutations in a gene encoding the chloride channel protein CLCN7 (OMIM 166600) with an incidence of ?1/20,000 births and severe infantile malignant autosomal recessive form due to mutations in the gene ATP6i encoding a[3] subunit of the V-ATPase vacuolar proton pump TC1RG1(OMIM 259700) with an incidence of ?1/250,000 births.[1-4] Pathologically there is a persistence of the primary spongiosa characterised by cores of calcified cartilage within bone. Abnormal remodeling of primary, woven bone to lamellar bone results in brittle bone that is prone to fracture. The severe form is usually detected in infancy or earlier because of macrocephaly, hepatosplenomegaly, deafness, blindness, severe anemia, leucopenia, and thrombocytopenia.[1] This form usually presents with pathologic fractures (because of brittleness of bones as a result of the abnormal bone structure due to failure of remodeling), or with failure to thrive.[5] Affected infants are predisposed to infection (since the generation of superoxide by peripheral blood leucocytes is defective in patients with osteopetrosis) and suffering from bouts of osteomyelitis, pneumonia, sepsis, and chronic meningitis.[6] The infections are usually of viral etiology; most commonly affect the respiratory tract, and are often prolonged. Infections, especially pneumonia and septicaemia, are a common cause of death.[7] Neurologic problems, such as hydrocephalus, facial paresis, seizures, and mental retardation, are also common.[5,8] Dental problems are also common. Rickets is a paradoxical complication in osteopetrotic bones due to inability of osteoclasts to maintain calcium and phosphate balance in extracellular fluid.The most severely affected patients die during infancy as a result of bone marrow failure and infections[9] less severely affected individuals rarely survive beyond the 2nd decade. Those who survive beyond infancy usually have learning disorders and may show show psychomotor delay but may have normal intelligence despite hearing and visual loss.[1] Cranial neuropathies are caused due to improper bone remodeling leading to narrowing of cranial nerve foramina and compression of nerves in skull foramina. For e.g. Optic nerve in optic canal leading to primary optic atrophy. Anaemia due to defective bone remodeling (reduced marrow spaces) is accompanied by compensatory extramedullary haematopoiesis in the liver and spleen. Other ophthalmic manifestations in osteopetrosis include chorioretinal degeneration, nystagmus, strabismus, proptosis, ptosis.[5] Sporadic ocular association of cataract has been reported. Severe visual loss is present in ~ 80% of cases of the infantile form of the disease and is due primarily to optic atrophy. The optic disc is chalky white with well defined margins without any gliosis with vessels being normal and physiological cup being present, pointing towards primary optic atrophy. Chorioretinal degeneration may also be a significant cause of visual loss in patients with infantile malignant osteopetrosis, and this may explain lack of response to decompression surgery.[5] The visual evoked potentials (VEPs) are the most useful way of monitoring optic nerve involvement while an electroretinogram (ERG) may help rule out associated neurological disease.[10] The visual loss is progressive and almost always occurs within the first year of life. Severely affected children may show absent or severely attenuated VEPs within the first three months, and in some this is apparent at birth. Because the rate of visual deterioration tends to plateau after 18 months to two years, some children, despite poor early neurophysiological findings, maintain a degree of visual acuity into later childhood. The pathology of the deafness is probably secondary to a combination of bony compression of the nerve, sclerosis of the middle ear ossicles, and/or chronic middle ear effusion. Early insertion of ventilatory “grommet” tubes should be considered.[3] Usually cases are diagnosed on X-rays, sometimes bone marrow biopsy may be required. Molecular diagnosis is also possible. Radiographs reveal diffuse bone sclerosis, loss of the normal corticomedullary differentiation, dense homogeneous appearance due to abnormally increased bone density with obliteration of medullary marrow spaces. Later films show the characteristic bone-within-bone appearance. Human leucocyte antigen-matched allogeneic haematopoietic stem cell transplantation(to provide the diseased bone with normal osteoclasts) is the only treatment known to significantly alter the course of the disease.[11,12] With younger children the focus should be on obtaining a BMT with the expectation being the preservation of existing sight rather than a reversal of disease process. Children with intact vision must be regarded as urgent priority in regard to BMT waiting lists. Optic canal decompression may be beneficial in some patients but not in others with chorioretinal degeneration. Optic nerve decompression is a hazardous procedure and reports suggest success only in mildly affected older children. Calcitriol (1,25-hydroxyvitamin D3) and Interferon-? -1b (1.5 µg/kg, three times per week) (macrophage-activating cytokine) have also been used with some benefit.[13] Glucocorticoids may help to stabilize hematopoietic function.6 Symptomatic care such as dental care, transfusions for anaemia, and antibiotic treatment of infections, is important for patients who survive infancy.[1]







Genetic counseling: all cases of infantile osteopetrosis are likely to be inherited in a autosomal recessive fashion. Thus there is a 1 in 4 (25 %) risk of having another affected child with each subsequent pregnancy. Molecular analysis is available. Antenatal diagnosis: A radiological diagnosis is possible in the third trimester. Molecular diagnosis is possible much early (CVS 11-13 weeks).[3] Insight into specific biochemical defects has come from the study of the several different animal models of osteopetrosis. Synthesis of the growth factor for cells of the mononuclear phagocytic system, colony-stimulating factor 1 (CSF-1), is disrupted in the osteopetrotic mouse as a result of a mutation in the CSF1 gene. This leads to an almost complete lack of osteoclast development, and reduced bone resorption. These findings indicate that CSF-1 is essential for the development of osteoclasts.[14,15] Other mouse models have demonstrated that two protooncogenes, c-src and c-fos, are also important in osteoclast differentiation and function.[15] It is hoped that the information gained from these animal models will translate into improved treatment for patients with osteopetrosis.[5] The autosomal dominant form of osteopetrosis (osteopetrosis tarda) usually presents during childhood or adolescence with fractures and mild anemia and, less frequently, as cranial nerve dysfunction, dental abnormalities, or osteomyelitis of the mandible.[16] Skeletalradiographs reveal a generalized increase in bone density and clubbing of metaphyses Alternating bands of lucent and dense bands produce a sandwich appearance to vertebral bodies.[17] Up to half of individuals with the benign form are asymptomatic.

Financial & competing interest disclosure

The authors do not have any competing interests in any product/procedure mentioned in this study. The authors do not have any financial interests in any product / procedure mentioned in this study

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CITE THIS ARTICLE

Dedhia C, Parekh N, Gohil N, Patel H, Parmar YPrimary Optic Atrophy in Osteopetrosis.DJO 2013;24:119-122

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Dedhia C, Parekh N, Gohil N, Patel H, Parmar YPrimary Optic Atrophy in Osteopetrosis.DJO [serial online] 2013[cited 2019 Nov 12];24:119-122. Available from: http://www.djo.org.in/articles/24/2/primary-optic-atrophy-in-osteopetrosis.html