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Abstract
Osteopetrosis refers to a collection of metabolic bone diseases with impaired osteoclastic activity resulting in abnormally dense and dysplastic bone. Cranial involvement results in severe complications, including compressive nerve palsies, hydrocephalus and tonsillar herniation. Ischaemic stroke is very rarely reported in osteopetrosis, resulting from vascular impingement. We report a young adult woman with CLCN7 (Chloride Voltage-Gated Channel 7) gene-related osteopetrosis and ischaemic stroke resulting from diffuse and focal arterial stenosis and severe myelophthisic anaemia. Acute management included blood transfusions, lay-flat positioning and fever treatment, which resulted in partial recovery of her initial neurological deficits. Our case highlights this very rare stroke syndrome’s unique mechanisms and treatment challenges.
- stroke
- calcium and bone
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Background
Osteopetrosis is a rare metabolic bone disease characterised by generalised osteosclerosis and dysplastic bone formation. Both autosomal recessive and autosomal dominant forms are known. Despite being named from the Greek words ‘osteo’ (‘bone’) and ‘petros’ (‘stone’), these dense bones are brittle and prone to fracture. Diagnosis is possible with standard radiography1 owing to its remarkably pathognomonic features such as the ‘bone-within-bone’ appearance and ‘sandwich vertebrae’ (figure 1A) resulting from overlapping parallel bands of dense bone. While skeletal and dental anomalies predominate, other complications may result, including altered calcium homeostasis, obliteration of marrow cavities and cranial foramina, resulting in haematological and neurological dysfunction. There are only three prior cases of ischaemic infarction with osteopetrosis, although arterial stenosis is more commonly reported (table 1). We describe a rare case of ischaemic stroke resulting from complications of osteopetrosis.
Previous reports of ischaemic stroke or vascular stenosis in osteopetrosis
Skeletal features of osteopetrosis (A) thoracolumbar spine, lateral view. (B) Thoracolumbar spine, anterior view. (C) Pelvis anteroposterior view. (D) CT of the brain, coronal view. Diffuse sclerosis (‘chalky white bone’) is evident on skeletal radiography with pathognomonic ‘sandwich vertebrae’ (white arrow) caused by endplate sclerosis. An increased calvaria thickness is seen on the CT.
Case presentation
A right-handed woman in her 30s presented to the emergency ward of our teaching hospital with right hemiparesis and absent speech for 8 hours. The patient was diagnosed with osteopetrosis 5 years before by skeletal radiography (figure 1) and bone marrow analysis. She had recently experienced unusual fatigue and weight loss for the last 3 months and had received blood transfusions for severe anaemia. However, no fractures, vision loss, anosmia, diplopia, deafness, facial paresis or facial numbness were reported. Her family history was negative for similar illnesses or consanguinity.
On examination, she was 155 cm tall with a body mass index of 14.1. Her blood pressure was 100/60 mm Hg and her heart rate was 144 beats per minute with a regular rhythm. All pulses were palpable, and no cervical bruit was present. She was febrile at 39.4°C, with splenomegaly (18 cm below the costal margin) and a mildly enlarged liver (1 cm below the costal margin). Neurological examination revealed motor aphasia with intact comprehension and dense right hemiplegia, with Medical Research Council (MRC) motor power grades 0 and 1 on the right upper and lower limbs, respectively, and a right extensor plantar response. Bedside visual acuity, funduscopy and hearing assessments were normal on subsequent examinations. The remainder of her neurological examination was unremarkable.
Investigations
A peripheral blood smear analysis was performed earlier to evaluate her anaemia. This revealed a leucoerythroblastic picture with nucleated red blood cells (15 per 100 red blood cells) and immature white blood cells (several blasts, myelocytes, metamyelocytes and band forms). This picture was suggestive of ‘myelophthisis’ or peripheral displacement of the haematopoietic bone marrow tissue. Aspiration of the bone marrow was attempted unsuccessfully, yielding a ‘dry’ tap. Hence, a bone marrow biopsy was performed. This showed significantly thickened bony trabeculae and osteoid seams, with increased mineralisation and fibrocollagenous tissue in cortical and cancellous bone. Another feature was marked narrowing and encroachment of the intertrabecular spaces, resulting in a hypocellular marrow with few haematopoietic elements and mild fibrosis. These findings suggested osteopetrosis with marrow failure.1
Present investigations revealed a haemoglobin of 34 g/L with normal platelet and granulocyte counts and electrolytes. An immediate MRI of the brain (figure 2A,B) showed diffusion restriction suggesting acute ischaemia in the left hemispheric deep white matter and internal capsule. Time-of-flight MR angiography (figure 2C) showed an absent flow signal in the supraclinoid segment of the internal carotid artery. Hence, CT angiography with three-dimensional reconstruction was performed (figure 2D–F). This revealed both diffuse (0.30 cm in diameter) and focal mild stenosis of the internal carotid arteries (47% at the narrowest point). The clinoid segments were particularly narrow and sharply angulated, especially on the left (0.16 cm in diameter, figure 2E,F). No collaterals were seen. The CT also revealed narrowing of the optic canals and internal auditory meatuses, with loss of sphenoidal and petrous bone pneumatisation (figure 2E,F). Next-generation exome sequencing was performed later and identified a mutation in the CLCN7 gene, consistent with autosomal recessive osteopetrosis.
Acute ischaemic stroke in the left hemisphere with vascular imaging. (A) Diffusion imaging (1000i). (B) Apparent diffusion coefficient map. (C) Time-of-flight (TOF) MR angiography of internal carotid arteries (ICAs) and circle of Willis. (D) CT angiography with three-dimensional reconstruction. (E) Sagittal and (F) coronal CT angiography of the cavernous and clinoid segments of the ICA. (G, H) Corresponding CT angiographic views of normal adult control. Diffusion restriction suggesting acute ischaemic infarction was present in the deep watershed between the anterior and middle cerebral artery territories (A–B). The TOF MR angiography showed a signal loss in the cavernous and clinoid segments of both ICAs (white arrows, C). On CT angiography, these corresponding segments showed contrast filling (white arrows, D). As compared with the control, the patient’s ICA appears to angulate sharply through the caroticoclinoid ring (black arrows). Loss of pneumatisation in sphenoid sinuses is also apparent.
Differential diagnosis
While ischaemic stroke resulting from vascular encroachment was the primary consideration given the background of osteopetrosis, other causes of fever-related strokes, such as infective endocarditis and meningitis causing stroke, were possible clinical differentials. However, endocarditis usually presents with a subacute course and bacteraemia, unlike our case. The absence of papilloedema, signs of meningeal irritation and other imaging clues to meningitis such as sulcal exudates and ventricular dilatation make the latter unlikely.
Treatment
She was managed with antiplatelet (aspirin 75 mg once a day). Packed red cells were transfused to raise the haemoglobin to 7.4 gL. Lay-flat positioning was maintained for 48 hours to augment cerebral blood flow until completing transfusions. Antipyretics and empirical broad-spectrum antibiotics were initiated, presuming an infective aetiology for fever, although no focus was evident. Her blood and urine cultures remained sterile, and fever defervescence occurred in 5 days. Her subsequent hospital stay was unremarkable.
Outcome and follow-up
She had complete recovery in language function, while motor function improved marginally to MRC grade 2 at discharge. A program for home exercise and occupational therapy to facilitate ambulation, transfers and activities of daily living was provided. At 1-year review, she regained functional independence for most activities and could walk a few steps without support. The power in the right upper and lower limbs were MRC grades 4 and 3, respectively, with significant spasticity. Her haemoglobin had fallen again to 5.6 g/L requiring transfusions once again.
Discussion
Osteopetrosis typically results from loss-of-function mutations that prevent the lysosomal fusion to the osteoclastic cell membrane, resulting in defective bone resorption and remodelling. Two phenotypes are known: autosomal recessive forms present in infancy and usually prove fatal. The autosomal dominant form is less severe, being asymptomatic in 50% and causing variable manifestations in the other.2 Genetic defects involving the osteoclast vacuolar proton pump (TCIRG1) and the (CLCN7) cause nearly 70% of autosomal-recessive osteopetrosis. While severity is marked and predictable with the TCIRG1 mutations, the CLCN7 mutations have a wide range of phenotypes encompassing infantile autosomal-recessive,3 ‘benign’ autosomal dominant and intermediate forms (our patient).1
Haematological complications include profound myelophthisic anaemia, bleeding, recurrent infections and hepatosplenomegaly from extramedullary haematopoiesis.2 Neurological dysfunction may occur as an early presenting feature.4 The most common features include blindness, proptosis, deafness, facial or trigeminal neuralgias, and nerve palsies.1 Optic atrophy and papilloedema may occur from elevated intracranial pressure or retinal vein encroachment. Hydrocephalus, tonsillar herniation and dural venous sinus stenosis are also seen.5 While our patient did not manifest these symptoms, subclinical narrowing of cranial nerve foramina was evident on her CT scans.
Arterial anomalies with osteopetrosis include both diffuse hypoplasia6 and focal impingement by dysplastic bone.7 The carotid artery is often involved unilaterally or bilaterally in the petrous canal.7 However, stenosis of the clinoid segment is uncommon.8 This segment traverses a ring formed by the anterior and middle clinoid processes and the caroticoclinoid ligament posteriorly. Failure of osteoclast-mediated remodelling may result in a persistent, foetal-type narrow ring.7 Alternatively, non-mineralised osteoid deposits may impinge on the artery while being inapparent on CT scans.7 Fixed stenosis may cause critical hypoperfusion from impaired cerebral autoregulation, especially in states of systemic haemodynamic compromise.9 Also, while a focal 47% narrowing in internal carotid arterydiameter would imply mild stenosis, the actual haemodynamic impact of the combined diffuse and focal stenosis may have been greater. This may explain why our patient developed watershed infarctions with severe anaemia and hyperthermia (which increases neuronal oxygen demand and vulnerability to ischaemia). Internal jugular vein compression or thrombosis are other possible contributory factors.2
In conclusion, we report a rare case of ischaemic stroke in an adult presentation of osteopetrosis. A ‘haemodynamic’ or hypoperfusion-related stroke was suggested by the watershed pattern of infarction on the MRI. Several factors, including arterial stenosis, severe anaemia and infection, were contributory. Acute management included blood transfusions, lay-flat positioning and fever treatment, which resulted in partial recovery of the initial neurological deficits.
Learning points
Diffuse and focal arterial stenosis is seen in osteopetrosis, resulting from dysplastic bone deposition and abnormal cranial remodelling.
Such fixed stenosis may impair cerebral autoregulation and predispose to cerebral ischaemia during states of haemodynamic instability (haemodynamic strokes). These typically involve ‘watershed’ regions between major arterial territories.
Bone marrow failure in osteopetrosis may cause severe anaemia and infections that may worsen the acute ischaemic insult. These factors are potentially reversible with early treatment.
The limited evidence available suggests a relatively favourable prognosis for neurological recovery with appropriate early management.
Ethics statements
Patient consent for publication
Acknowledgments
The authors thank Dr Aditya Nair, Dr Sanjith Aaron and Dr Biju George for their contributions to the work.
Footnotes
Contributors GAN and RNB prepared the draft for submission. AJ selected and helped prepare the image files and provided related inputs. SAL reviewed the manuscript. All authors approved the final version.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.