The purpose of staging of FD/MAS is to determine the full extent and impact of disease at diagnosis to guide tests and treatments and to minimize risk of complications. Staging should be considered at the time of presentation with suspected FD/MAS taking into account age and clinical presentation. The key components of staging are listed below.
Evaluation of the skeletal system
(See Additional file
2: Flow chart: Skeletal evaluation FD lesion(s))
Assessment of the skeletal system requires a full medical history, physical examination, laboratory investigations and radiological and nuclear imaging. Assessment of skeletal symptoms should include a skeletal map with areas marked for bone pain (see below), joint pain and bone/ joint deformity; a fracture history including site, date, level of trauma (e.g. spontaneous, fragility, severe trauma) and fracture healing (complete / incomplete / non-healing); previous orthopaedic procedures (type and date) including details of metalwork insertion (location and type). The following information should be collected on previous use of bone specific therapy: ever use, generic name of drug, date of first and last use and total number of years of use. Previous or current participation in clinical trials should be recorded and include the date of the trial(s) and treatment(s) tested should be documented.
Assessment of severity of pain should include a VAS 0–10 and Brief Pain Inventory [
13] for adults or Wong Baker Facies [
14] for children. The presence of night pain should raise a red flag for possible complications such as imminent fracture, bleeding into a cyst or very rarely malignant transformation. A potential neuropathic character to pain should be assessed using the PainDetect questionnaire [
15]. The contribution of pain from surgical scars, referred pain from adjacent joints, local tendinosis, chronic pain disorders/ fibromyalgia should also be evaluated.
In the presence of focal and/or acute onset pain, acute or impending fracture, aneurysmal bone cyst or stress fracture especially in a deformed long bone should be considered. Mechanical pain can be provoked using the rotational stress test, for instance in lesions of the proximal femur. The FABER test: motion hip in Flexion, ABduction and External Rotation, is also recommended. Although very rare, sarcomatous change should be considered in the presence of diffuse and/or chronic pain, especially if progressive and unrelenting and also present at night. This should be further evaluated using CT/ MR imaging and discussed with the local sarcoma team. Mechanical/ weight bearing bone pain can signal a stress or impending fracture. This should trigger consideration for correction of alignment, and/or consideration for the necessity of a surgical procedure, possibly involving the use of an intramedullary titanium nail or custom-made titanium angled blade plate, based on the ‘bridging the defect’ principles, to stabilize the involved bone.
Physical examination of the skeletal system should include gait, deformity including leg length discrepancy to inform potential complications, areas of tenderness and range of movement of adjacent joints and presence of spinal kyphosis and scoliosis [
16‐
18].
Bone-related laboratory testing [
19‐
22] should include a standard biochemistry screen of renal profile, total alkaline phosphatase, bicarbonate, albumin-adjusted serum calcium, phosphate (see below), 25OH-vitamin D and parathyroid hormone.
Abnormal phosphate homeostasis, specifically renal phosphate wasting leading to hypophosphatemia, is important to diagnose as it is an important predictor of future fracture risk, as well as other complications [
20,
22,
23]. In all subjects with suspected polyostotic disease, baseline overnight fasting phosphate levels should be checked. In case of use of phosphate supplements, serum phosphate should be measured whilst the patient is off supplements for at least a day. Values should be related to age specific reference ranges. Phosphate homeostasis is ideally assessed in the fasting state by concomitantly collecting serum phosphate and creatinine and second void urine phosphate and creatinine. This will enable calculation of the tubular reabsorption of phosphate (TmP/GFR) and calculated values should again be related to age-related reference ranges [
http://members.iinet.net.au/~bill/java/tmp_gfr.html].
It is important to exclude other causes of renal phosphate wasting such as hyperparathyroidism and renal tubular acidosis. This can usually be done through history, examination and biochemical assessment e.g. dipstick urinalysis for glycosuria, measurement of serum bicarbonate and urinary amino acids. It should be noted that hypophosphataemia may be episodic and assessment may need to be repeated if skeletal symptoms change and during linear growth. If serum FGF-23 is to be measured the blood sample should be collected at least 7 days off phosphate/ vitamin D supplements, using an accredited assay/ laboratory if available.
Total alkaline phosphatase (ALP) is the minimum recommended biomarker for bone turnover. Other bone turnover markers are optional and include bone-specific ALP (with age related reference ranges), procollagen Type 1 N-terminal propeptide (PINP), C-terminal telopeptide (CTX-I). If these are not available, consider storing serum at − 20 °C for later analysis.
Skeletal imaging is the investigation of choice to determine skeletal burden depending on the clinical presentation [
24‐
26]. All skeletal burden is detectable by age 15 years and clinically significant lesions by the age of 5 years [
24]. To evaluate the extent of FD, whole body imaging using bone scintigraphy, whole body MR or low-dose 2D/3D radiography (e.g. EOS), to determine the presence and extent of skeletal involvement should be considered for all patients ≥ age 5 years. It should be noted that skull base lesions are likely to be missed by the EOS. Due to the possibility of false negative results, whole body imaging should be delayed in asymptomatic children until age 5 [
24] and when the child can tolerate an MRI without general anaesthesia. Whole body or targeted skeletal imaging prior to age 5 should be considered when the benefits of early diagnosis outweigh the risks of waiting till the child is older. Scoring of the skeletal burden should be performed using the Collins’ validated method [
25].
Areas of clinically significant axial and appendicular FD identified on bone scintigraphy should be imaged with conventional radiographs in two planes of the whole bone. A localized fine cut CT scan is preferred in case of clinical evidence of nerve entrapment.
Specific recommendations for spinal FD (Fig. 3c)
Evidence of scoliosis on physical examination should be confirmed with conventional radiographs. Once established, progression of scoliosis should be assessed with regular, periodic radiographs and pulmonary function testing. The periodicity of these examinations should be adjusted based on the severity and rate of progression, or lack thereof, in a given individual. Early consultation with spinal team and therapists is recommended and surgical fixation should be considered if Cobb angle is above 30 degrees depending on the rate of progression and location of the curve. [
18,
27,
28].
Craniofacial FD (Flow chart Craniofacial FD)
The aim of staging cranio-facial lesions is to define and record the extent, distribution and impact of FD in the craniofacial skeleton. Following a history and physical examination the following tests are recommended where clinically relevant: objective assessment of facial asymmetry using clinical photography and 3D photography and assessment of psychological impact including using the Craniofacial Experience Index [
29]. Radiological assessment includes standard radiological facial and orthognathic series and fine cut CT 1 mm or less slice thickness. If craniofacial lesions are adjacent to relevant structures or nerve pathways, referrals should be considered to the following specialties: craniofacial surgery, plastic surgery, ophthalmology, ENT & audiology, maxillofacial surgery and neurosurgery. A referral to a specialised craniofacial service should be considered if there is evidence of nerve impairment of functional impairment.
Dental FD
In case of dental involvement, panoramic radiographs and intraoral (periapical and bitewing) radiographs will provide assessment of both arches, as well as adjacent anatomic structures including maxillary sinuses, nasal cavity, mental foramina and mandibular canals. In addition, useful information will be provided regarding the presence of carious lesions, periodontal disease, or periapical disease, all important risk factors for osteonecrosis of the jaw (ONJ). More advanced imaging techniques include the use of cone beam computerized tomography (CBCT) assessing cortical and cancellous architecture with lower radiation exposure, magnetic resonance imaging (MRI), 99mTc-methylene diphosphonate bone scintigraphy, and positron emission tomography, (PET).