Osteopetrosis with Arnold Chiari malformation type I

Abstract

Osteopetrosis is a rare genetic disorder resulting in increased bone density and decreased bone remodelling. Bone expansion results in the crowding of neural foramina causing cranial nerve compression. Here, we describe a female infant in her mid infancy presented with no eye contact since birth, and abdominal distension for 2 months. On CT evaluation, sclerotic bones with bilateral optic canal narrowing were present. A crowded posterior fossa with Arnold Chiari type I malformation was seen on MRI evaluation, suggesting a rare association of osteopetrosis with Arnold Chiari’s malformation.

Background

Osteopetrosis is a rare sclerosing disease of the bone characterised by high mineral density of the bone due to osteoclastic impairment. Incidence of osteopetrosis ranges from 1:20 000 to 1:200 000 based on inheritance pattern.^{1 2} It presents various symptoms, including skeletal, neurological and haematological manifestations. The neurological manifestations commonly include cranial neuropathies involving optic, trigeminal, facial and cochlear nerves due to bony involvement of the neural foramina. Arnold Chiari’s malformation in osteopetrosis is an extremely rare entity. Literature search (Pubmed, Embase and Cochrane) revealed only seven cases prior to this where osteopetrosis has been associated with Arnold Chiari type I malformation.^3–9 Here, we report a rare case of infantile osteopetrosis with Arnold Chiari I malformation.

Case presentation

A woman in her mid-infancy born to non-consanguineous parents presented with complaints of no eye contact since birth, followed by a distended abdomen for 2 months. No history of feeding abnormalities or constipation was elicited. No significant family history was present. Vitals were stable. On examination, a bulging anterior fontanelle was noted along with hepatosplenomegaly. Developmental milestones were achieved for age. Anthropometry showed a large head size disproportionate to weight and length (weight: 5 kg, height: 60 cm, head circumference: 41.5 cm). On palpation, the liver was 4.5 cm below the right costal margin, and the spleen was 4 cm below the left costal margin, with a soft consistency.

Investigations

The ophthalmological evaluation showed bilateral primary optic atrophy Auditory assessment showed bilateral sensorineural hearing loss. Laboratory evaluation showed a total serum calcium level of 8.8 mg/dL (8–11 mg/dL) and serum phosphate of 2.98 mg/dL (3.5–5 mg/dL). Other possible causes of hepatosplenomegaly, like TORCH infections and haemolytic anaemia, were ruled out. CT of the brain was done, which showed the reduced calibre of the optic nerve in the optic canal bilaterally and increased bone density in petrous bone. MRI brain was done to rule out any intracranial space-occupying lesion, which showed hydrocephalus, small posterior fossa, tonsillar herniation and thinned bilateral optic nerves in the optic canal (figure 1A–J). Skeletal radiographic analysis showed increased bone density on multiple bones with a lack of corticomedullary differentiation on the long bones (figure 1K,L). There was also fraying and splaying of the metaphysis of the visualised long bones and beading of the anterior costochondral junction suggestive of rickets. Given the financial constraint, we could not do the 25-OH vitamin D level and PTH.

Figure 1.

Non-contrast CT (NCCT), MRI and X-ray image showing osteopetrosis with Arnold Chiari malformation. Axial NCCT scan (A, B, D) and coronal CT scan (C) showed the reduced calibre of the optic nerve with optic canal and increased bone density in the bilateral petrous bone. MRI (E) showing hydrocephalus. MRI (F, I) showed tonsillar herniation. MRI (H, G) showed thinned bilateral optic nerves with the optic canal. MRI (J) showed developed cochlea and semicircular canals. Skeletal X-ray image (K, L) showed increased bone density with a lack of corticomedullary differentiation. Fraying and splaying of the metaphyseal ends of visualised long bones with beading at anterior costochondral junctions.

Treatment

After hospitalisation, complete blood count (CBC) showed low haemoglobin (Hb: 75 g/L) and platelet count (platelet count: 28x10⁹/L), for which she received one unit of blood transfusion (packed red blood cell) and post-transfusion haemoglobin was raised to 82 g/L. Clinico-radiological diagnosis of osteopetrosis and rickets was made. Bone marrow aspirate was dry, and the biopsy showed fibrous tissue with scanty foci of haematopoiesis. The sample was saved for genetic testing. The patient was referred to a higher centre for haematopoeitic stem cell transplantation. She was started on 25-OH vitamin D supplementation along with calcium.

Discussion

Osteopetrosis is a rare metabolic bone disorder characterised by reduced osteoclastic bone resorption, resulting in bones with high mineral density. Based on inheritance, it is classified into autosomal dominant and autosomal recessive (infantile malignant and intermediate). All varieties of human osteopetrosis share a common pathogenic nexus in the osteoclasts, even though they have various molecular abnormalities and clinical characteristics. Infantile osteopetrosis is an autosomal recessive illness with four genes (TCIRG1, OSTEM1, CLCN7, RANK and RANKL) that have been identified till now.¹⁰

A diagnosis of osteopetrosis can be made with the thorough clinical, endocrinological and radiological examination and genetic testing is usually not required in most cases.¹¹ In the present case also the diagnosis was made based on history, clinical, radiological and laboratory evaluation.

Infants with osteopetrosis are predisposed to structural brittleness and fracture, resulting in skeletal deformities and dental abnormalities. The typical radiological findings include several past fracture lines, sclerotic appearances on the long bone and bone inside bone appearance. Other radiological abnormalities include hypoplastic maxillary sinus, tooth malformation and numerous caries.¹² Although classical features of osteopetrosis were not seen, the radiographic evaluation showed sclerotic changes in multiple bones in our patient. CT showed increased density in the petrous part of the temporal bone. In the present case, the patient did not have eye contact since birth is likely due to the optic canal narrowing and bilateral optic nerve atrophy.

Dlouhy et al, observed that the mechanism of the Chiari malformation in osteopetrosis is unclear.⁵ Various hypotheses having proposed including calvarial thickening causing mass effect and subsequent downward herniation of cerebellar tonsils. Moreover, the absence of osteoclastic activity leads to an underdeveloped occipital bone, and associated thickening may result in a small posterior fossa. Chiari I malformation can present with various symptoms, including orthostatic hypotension, syncope and death. Symptomatic Chiari malformation needs surgical correction. Abnormal enchondral formation of bone causes haematological disorders, including anaemia, thrombocytopenia, increased susceptibility to infection and extramedullary haematopoiesis. Our patient presented with abdominal distension due to hepatosplenomegaly. CBC also showed bicytopenia.

Rickets can be a paradoxical complication of infantile osteopetrosis, where dysfunctional osteoclasts cannot maintain calcium-phosphorus homeostasis despite positive total body calcium balance.¹³ This overlapping pattern is known as osteopetrorickets.¹⁴ Haematopoeitic stem cell transplant is the only curative option for an infantile malignant form of osteopetrosis.¹⁵ Stem cell transplant was unavailable in our hospital, hence the patient was referred to a higher centre for further management.

Patient's perspective.

We are very thankful to the hospital and the doctors involved in our case. They have diagnosed the case properly though it is a very rare case. We are taking the case to a higher centre with bone marrow transplantation. We are happy as this type of report will increase diagnostic accuracy in similar cases and help with early treatment.

Learning points.

• Osteopetrosis with Chiari I malformation is rare and life-threatening.

• A complete skeletal survey, clinical suspicion and high-end radiological knowledge are essential for accurate diagnosis.

• In addition, this article emphasises the need for prompt diagnostic workup and clinical management of such patients.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).