Bilateral Cavernous Internal Carotid Aneurysms in a Child with Juvenile Paget Disease and Osteoprotegerin Deficiency

Abstract

Juvenile Paget disease or familial hyperphosphatasia is a rare autosomal recessive disorder, which represents a distinct clinical condition, not simply a juvenile-onset form of Paget disease. Osteoprotegerin deficiency leads to marked osteoclast activation and greatly accelerated bone remodeling. We report a case of a child with a severe form of this condition and bilateral cavernous internal carotid artery aneurysms. The association suggests a role of osteoprotegerin deficiency in vessel wall abnormalities.An 11-year-old boy presented with the chief complaint of difficulty looking straight with both eyes. Physical findings included strabismus of the left eye, developmentally short stature, bowed limbs, head disproportionately large for the trunk, and normal mental aptitude. Conventional noncontrast CT and CT angiography (CTA) of the head were performed. Symmetric aneurysms were demonstrated in the internal carotid arteries in the cavernous sinuses (Fig 1). There was remodeling and smooth thinning of the sphenoid bone between the aneurysms and the sphenoid sinus, abnormal definition of the inner ear structures bilaterally, and ground-glass changes within the medullary space of the calvaria. Conventional angiography confirmed the aneurysms (Fig 2).Despite the name, juvenile Paget disease is distinct from the relatively common adult-onset disease known as Paget disease. Juvenile Paget disease, hereditary hyperphosphatasia or hyperostosis corticalis deformans juvenilis, is a rare autosomal recessive disease of bone, which presents in infancy or early childhood (OMIM #239000; NCBI; www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?idϭ239000). Accelerated remodeling of the skeleton results in bone deformities, pain secondary to fractures, osteopenia of the long bones, corticomedullary indistinctness, and coarsening of the trabecular bone. The juvenile disease affects the entire skeleton, whereas the conventional Paget disease involves more localized patterns of osteopathy, with both destructive and sclerotic phases.1 Juvenile Paget disease has been shown, in at least some cases, to be due to genetic deficiency of osteoprotegerin (not a known mechanism of conventional Paget disease). In some cases, including this patient, there is a homozygous deletion of a gene (TNFRSF11B) on chromosome 8q; the missing gene normally encodes osteoprotegerin. Past analysis had shown the patient presented here to have no detectable serum levels of osteoprotegerin. 1Osteoprotegerin, a soluble glycoprotein, acts as a decoy receptor that blocks the activation by receptor activator for nuclear factor B ligand (RANKL) of osteoclasts. The osteoprotegerin/RANKL/receptor activator of nuclear factor B system is central to regulation of osteoclast activity and bone turnover, and many cytokines and hormones affect this system. In addition to their role in a wide variety of skeletal disorders, osteoprotegerin and RANKL are being intensively studied for roles in the immune and vascular systems.2 For example, osteoprotegerin/RANKL balance may be a factor in a...

Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK

“…(3) In JPD1, VMC causes retinal blindness in early adult life, (16) and perhaps carotid artery aneurysms during childhood. (15) …”

“…Typically, unique homozygous TNFRSF11B mutations represent a “founder” in different geographical regions. (13) This OPG deficiency form of JPD uniquely leads to vascular microcalcification (VMC) (14) that perhaps explains carotid aneurysms in childhood (15) and retinopathy with blindness in adult life. (16, 17) A genetic basis for other instances of JPD remains presumptive.…”

Rare Inherited forms of Paget’s Disease and Related Syndromes

“…Vascular calcification is another recognised feature which becomes more penetrant with increasing age. Aneurysms of the internal carotid artery have also been reported [23]. Other features which have been reported include contractures, which seem most likely to be secondary to deformity, sinus aplasia, hormone deficiencies and hypertension [24].…”

Auricular ossification: A newly recognized feature of osteoprotegerin‐deficiency juvenile Paget disease

“…He subsequently had nearly lifelong treatment with IV and oral BPs. At age 11 years, unilateral strabismus led to discovery of bilateral carotid artery aneurysms that were treated successfully with occlusion and bypass surgery [Allen et al, ]. At age 18 years, retinal angioid streaks were noted.…”

“…Without bone antiresorptive treatment, JPD may be fatal during childhood [Whyte et al, ]. Notably, JPD patients can have features of pseudoxanthoma elasticum (PXE: OMIM #264800) including acquired diffuse vascular microcalcification leading to retinopathy, blindness, coronary artery occlusion, and perhaps to intracranial aneurysms [Allen et al, ; Kerr et al, ; Whyte, ].…”