Oral Presentation 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

A bony conundrum that keeps on growing: The ABCs of PFD (#45)

Matthew Balcerek 1 , Thomas Hadwen 1 , Emma Duncan 2
  1. Department of Endocrinology and Diabetes, Sunshine Coast University Hospital, Birtinya, QLD, Australia
  2. Department of Endocrinology and Diabetes, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia

Case Summary

A 21-year-old Caucasian male with polyostotic fibrous dysplasia (FD) presented with recurrent craniofacial aneurysmal bone cysts (ABCs).

FD was first diagnosed at age 4 years, with widespread disease (Fig-1). Orthopaedic complications have included multiple right femoral fractures requiring pinning in childhood, prophylactic pinning of his right humerus as a young adult prompted by bone pain, and subsequent minimal-trauma periprosthetic fractures (riding over bumps on his bicycle). Neurologically, right optic nerve compression developed at age 14 years requiring surgical decompression, with residual right visual loss (light perception only). Left optic nerve compression occurred at age 19 years, managed conservatively with glucocorticoids, with preserved vision. There has been no hormonal over-secretion or café-au-lait pigmentation.

In November 2014, he developed a rapidly enlarging painless left frontal bone soft-tissue mass. Computed Tomography (CT) revealed extensive changes of FD involving the skull vault and base, and a cystic mass above the left orbit consistent with an ABC. The mass increased rapidly, from 47x41x48mm to 67x54x71mm over a two-week period (Fig-2, Fig-3). Given the rapid expansion and threatened vision, he underwent craniotomy with excision of an 8x10cm lesion. Histology was consistent with ABC. Magnetic resonance imaging (MRI) five months post-operatively showed two small cysts posterior to the craniotomy site, and new cystic changes in the left sphenoid (15mm) and right temporal bone (13mm).

In July 2015, he developed a painful expansile lesion arising from the angle of the left mandible. CT showed typical changes of FD and four contiguous cystic structures (31mm, 25mm, 12mm, 8mm) consistent with ABCs. The most posterior lesion caused extensive dehiscence of the inferior mandibular cortex (Fig-4).  These lesions were excised; histology again revealed ABC, without malignant features.

In the setting of a new lytic left tenth rib lesion and the aggressive nature of his previous ABCs, intravenous zoledronic acid (ZA) 5mg was administered in November 2018, with modest effect on bone turnover makers (ALP 394 to 362U/L, CTX 830 to 779ng/L, total P1NP 500 to 309ug/L over 12 months). No ABCs developed over the ensuing two years and the rib lesion regressed.

In September 2018, he developed sudden onset aural ‘fullness’ and right ear tinnitus, with impaired balance and mild sensorineural hearing loss. CT and MRI revealed enlargement of the previously dormant 13mm temporal bone cyst (now 32x12x13mm) with erosion into the right posterior semicircular canal (Fig-5). A further dose of ZA 5mg was administered. There was mild symptomatic improvement, coupled with radiographic regression (28x9x11mm on MRI seven months later).

 

Discussion

FD is a rare skeletal disorder, caused by a somatic activating mutation of GNAS, which leads to abnormal osteoblast differentiation and replacement of normal medullary bone with fibro-osseous connective tissue1. Bony involvement can be monostotic (70%) or polyostotic (30%), and symptoms can include localised pain, deformity and pathological fracture. Craniofacial bones are involved in 50% of polyostotic FD, particularly the maxilla and mandible. Frontal bone involvement is uncommon, and the temporal bone is rarely affected2. Visual complications are the most common neurological manifestation of craniofacial FD3. Depending on which tissues harbor the mutation, FD may also be associated with hormonal hypersecretion and café-au-lait pigmentation (McCune-Albright Syndrome)4.

Our patient experienced multiple complications of FD, including pathological right humeral and femoral fractures, and bilateral optic nerve compression secondary to optic canal stenosis, with permanent right visual loss – and now has developed recurrent ABCs.

Concomitant FD and ABC is rare, especially in the craniofacial region. ABCs are usually primary osseous lesions, though 30% occur secondary to underlying pathologies including FD. Despite their benign pathology, ABCs can manifest as rapidly enlarging locally destructive masses. Osteosarcoma is an important differential as malignant transformation can occur in FD (<1%)5. ABC treatment is usually surgical resection, with preoperative transarterial embolisation often used to reduce intraoperative bleeding. Recurrence rates range 5-40%, depending on the surgical approach6. Spontaneous remission has been reported, with close surveillance an option if the ABC poses low risk of fracture or other compromise7.

Our patient’s ABCs were aggressive and associated with threatened visual loss (frontal ABC), significant pain (mandibular ABC), and auditory/vestibular complications (temporal ABC).  A surgical approach was required for our patient’s frontal and mandibular ABCs, whereas active surveillance of the temporal ABC was chosen due to symptomatic and radiographic improvement.

Although FD is an osteoblastic disorder, bisphosphonates have been trialed due to histologic findings of inappropriate osteoclastogenesis in FD tissue8. A single RCT (n=40) evaluated daily alendronate in 6-month cycles for two years in adults and children with polyostotic FD9. Findings included reduced urinary NTX-telopeptides and improved areal BMD in FD-affected regions. However, no significant effect on serum osteocalcin, functional parameters or pain relief was observed9.  

Varying degrees of pain relief and lesion ossification have been observed in small prospective studies of patients with inoperable ABCs receiving IV pamidronate or ZA10, with no radiographic progression up to 6 years post-treatment11. However, these studies did not differentiate between primary and secondary ABCs, or specify the underlying bone disorder.

FD and ABCs may have increased RANKL expression12, and denosumab has shown promise in lowering biochemical markers of bone turnover in bisphosphonate-refractory FD13. Radiographic healing, ABC regression and pain relief has been reported in observational studies of denosumab in adults and children with spinal and pelvic ABCs14-15.  Concerns with denosumab include the possibility of rebound increased bone turnover and potential rapid disease progression on discontinuation, as well as complications of long-term bone suppression such as osteonecrosis of the jaw.

Further prospective clinical trials may help clarify the place of bisphosphonates and denosumab both in FD and in ABC, especially in patients with locally advanced, irresectable or recurrent disease.  

 

Take-home messages

  • Our case highlights the challenging aspects of craniofacial FD with neurological involvement and secondary ABC
  • ABC should be considered in patients with rapidly growing soft tissue masses and underlying FD
  • Optimal management is complete surgical excision
  • Antiresorptive therapy has been trialled in aggressive and/or irresectable disease, and may alter the clinical course of both FD and ABCs

 

Figures

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