Psychosocial effects of whole-body MRI screening in adult high-risk pathogenic TP53 mutation carriers: a case-controlled study (SIGNIFY).

BACKGROUND: Germline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for female TP53 pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44 TP53 pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult TP53 pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms. METHODS: Psychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks' follow-up. RESULTS: WB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity throughout. Although their mean levels of cancer worry were not high, carriers had significantly more cancer worry at most time-points than controls. They also reported significantly more clinically significant intrusive and avoidant thoughts about cancer than controls at all time-points. There were no clinically significant adverse psychosocial outcomes in either carriers with a history of cancer or in those requiring further investigations. CONCLUSION: WB-MRI screening can be implemented in TP53 pv carriers without adverse psychosocial outcomes in the short and medium terms. A previous cancer diagnosis may predict a better psychosocial outcome. Some carriers seriously underestimate their risk of cancer. Carriers of pv should have access to a clinician to help them develop adaptive strategies to cope with cancer-related concerns and respond to clinically significant depression and/or anxiety.

Multiple primary malignancies associated with a germline SMARCB1 pathogenic variant.

A 51-year old presented with a 6-month history of increasing pelvic/lower back pain with nocturnal waking and episodes of anorexia and vomiting. Examination revealed right torticollis and Horner's syndrome, and a large abdominal mass arising from the pelvis. Magnetic resonance and positron emission tomography imaging revealed (A) a 14 cm heterogeneous enhancing mass, abutting the left kidney with standardised uptake value max = 2.9, (B) a large heterogeneous enhancing pelvic mass (C) mesenteric adenopathy standardised uptake value max = 10.3 and (D) 6 cm right lung apex mass standardised uptake value max = 4.3. Computerised tomography-guided biopsy of lesion A was reported as neurofibroma with occasional atypia, lesion B a benign uterine leiomyoma and lesion C follicular lymphoma world health organisation Grade 2. Although she had been given the diagnosis of Neurofibromatosis Type-1 (NF1) 25-years previously following removal of an intradural extramedullary schwannoma she had no cutaneous stigmata of NF1. Genetic analysis of blood lymphocyte DNA identified a pathogenic variant in SMARCB1 confirming a diagnosis of schwannomatosis. Following 6-months chemotherapy for lymphoma, surgery was performed to remove lesion A. Histology revealed a malignant peripheral nerve sheath tumour with areas of low and high-grade change. An incidental, well-differentiated small bowel neuroendocrine carcinoma was also excised. Close surveillance continues with no recurrence after 6 years. This case study describes a novel finding of three separate synchronous primary malignancies in a patient with schwannomatosis and a proven SMARCB1 pathogenic variant.

Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls.

In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. In TP53 mutation carriers, 6 of 44 (13.6, 95% CI 5.2-27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1, 95% CI 20.5-49.9%) and seven controls (15.9, 95% CI 6.7-30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. This should be adopted into national guidelines for management of adult TP53 mutation carriers in addition to the current practice of contrast enhanced breast MRI imaging.

Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum.

Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype-phenotype correlation, this cannot yet be confirmed.

Can the diagnosis of NF1 be excluded clinically? A lack of pigmentary findings in families with spinal neurofibromatosis demonstrates a limitation of clinical diagnosis.

BACKGROUND: Consensus clinical diagnostic criteria for neurofibromatosis type I (NF1) include café-au-lait macules and skinfold freckling. The former are frequently the earliest manifestation of NF1, and as such are of particular significance when assessing young children at risk of the condition. A phenotype of predominantly spinal neurofibromatosis has been identified in a small minority of families with NF1, often in association with a relative or absolute lack of cutaneous manifestations. An association with splicing and missense mutations has previously been reported for spinal neurofibromatosis, but on the basis of molecular results in only a few families. METHOD: Patients with spinal NF1 were identified through the Manchester nationally commissioned service for complex NF1. RESULTS: Five families with spinal NF1 were identified, with a broad spectrum of NF1 mutations, providing further evidence that this phenotype may arise in association with any genre of mutation in this gene. Pigmentary manifestations were absent or very mild in affected individuals. Several further affected individuals, some with extensive spinal root tumours, were ascertained when additional family members were assessed. CONCLUSIONS: Clinical NF1 consensus criteria cannot be used to exclude the diagnosis of spinal NF1, especially in childhood. This emphasises the importance of molecular confirmation in individuals and families with atypical presentations of NF1.

Spinal bone defects in neurofibromatosis type I with dural ectasia: stress fractures or dysplastic? A case series.

OBJECTIVES: Neurofibromatosis type I (NF1) is a multisystem neurocutaneous disorder with varied musculoskeletal manifestations. Dural ectasia is a known association, whilst pedicular anomalies have been described, although not as frequently as other skeletal manifestations. However, reports of pedicular and other spinal clefts or fractures in combination with dural ectasia in NF1 are scarce. We aimed to identify osseous defects in the posterior elements of NF1 patients with dural ectasia. METHODS: Images of patients with NF1 and back pain were reviewed for osseous defects in the posterior elements. RESULTS: Four patients were identified with NF1, back pain, dural ectasia and bone defects. The imaging appearances of the defects are illustrated. CONCLUSIONS: Defects in the spinal posterior elements of patients with NF1, back pain and dural ectasia may be dysplastic, stress fractures or, most probably, multifactorial in origin. Computed tomography demonstrates these defects most clearly.

Under-reporting of osteoporotic vertebral fractures on computed tomography.

PURPOSE: Osteoporotic vertebral fractures are frequently asymptomatic. They are often not diagnosed clinically or radiologically. Despite this, prevalent osteoporotic vertebral fractures predict future osteoporotic fractures and are associated with increased mortality and morbidity. Appropriate management of osteoporosis can reduce future fracture risk. Fractures on lateral chest radiographs taken for other conditions are frequently overlooked by radiologists. Our aim was to assess the value of computed tomography (CT) in the diagnosis of vertebral fracture and identify the frequency with which significant fractures are missed. MATERIALS AND METHODS: The thoracic CT scans of 100 consecutive male and 100 consecutive female patients over 55 years were reviewed. CT images were acquired on General Electric Lightspeed multi-detector (MD) CT scanners (16 or 32 row) using 1.25mm slice thickness. Midline sagittal images were reconstructed from the 3D volume images. The presence of moderate (25-40% height loss) or severe (>40% height loss) vertebral fractures between T1 and L1 was determined using an established semi-quantitative method and confirmed by morphological measurement. Results were compared with the formal CT report. RESULTS: Scans of 192 patients were analysed (95 female; 97 male); mean age 70.1 years. Thirty-eight (19.8%) patients had one or more moderate to severe vertebral fractures. Only 5 (13%) were correctly reported as having osteoporotic fractures in the official report. The sensitivity of axial CT images to vertebral fracture was 0.35. CONCLUSION: Incidental osteoporotic vertebral fractures are under-reported on CT. The sensitivity of axial images in detecting these fractures is poor. Sagittal reformations are strongly recommended to improve the detection rate.

Charcot neuroarthropathy: an unusual case and a review of the literature.

Charcot neuroarthropathy is a devastating consequence of diabetes, requiring early identification and immediate management. A differentiation should be made from osteomyelitis and other pathologies. The authors describe a case of Charcot foot with radiological findings of complete fragmentation of the calcaneum. Further investigation with magnetic resonance and white cell-labeled imaging revealed osteomyelitis. Below-knee amputation was the only therapeutic option in this hindfoot collapse complicated with osteomyelitis.

Vertebroplasty and kyphoplasty.

Vertebral compression fractures are common in elderly populations and in particular in postmenopausal women as a consequence of osteoporosis. Percutaneous vertebroplasty and kyphoplasty are minimally invasive procedures that are increasingly used to treat persistent or severe acute pain from these fractures. Vertebroplasty works by augmenting the weak osteopenic vertebrae with polymethylmethacrylate (PMMA) bone cement and thus preventing further microfractures and associated pain. The aim of kyphoplasty is pain relief combined with restoration of vertebral body height and reduction in kyphosis. This is achieved by 'expanding' the fractured vertebra with a balloon and then filling of the resultant cavity with PMMA cement. Vertebroplasty and kyphoplasty are undertaken under local and general anaesthesia, respectively. Both procedures have a very low complication rate if properly performed by well trained clinicians using appropriate cement and technique and highquality imaging. Patient selection and the selection of the level at which the percutaneous vertebroplasty is to be done are of utmost importance for maximal therapeutic benefit. Additional trials are required to establish conclusively the effectiveness of both procedures compared with conservative medical therapy and each other.

The sesamoid index in psoriatic arthropathy.

OBJECTIVE: The sesamoid index was originally described as an aid to the diagnosis of acromegaly. We performed this study to assess the value of the thumb sesamoid index in the diagnosis of psoriatic arthropathy. DESIGN: Retrospective measurement of the sesamoid index (length x width of the medial thumb sesamoid), along with the age and sex were recorded for patients as described below. Patients with psoriasis were subdivided into those with or without radiographic evidence of hand arthropathy. PATIENTS: Fifty-nine consecutive patients attending rheumatology clinics with arthralgia and psoriasis were studied. Comparison groups with radiographic evidence of rheumatoid arthritis (52 patients), osteoarthritis (44) or normal hands (55) were also recorded. RESULTS: Twenty-one of 59 patients with psoriasis and arthropathy had a sesamoid index>40, compared with two of 52 with rheumatoid arthritis, none of 44 with osteoarthritis and none of 55 normals. CONCLUSIONS: Psoriatic arthropathy is a recognised cause of bone enlargement, usually in the phalanges due to periostitis and proliferative enthesopathy. We have confirmed that psoriatic hand arthropathy can cause significant enlargement of the thumb sesamoids, a feature which is easily quantified and may assist diagnosis.

Paget's disease of bone.

Paget's disease of bone is one of the most common diseases to affect bone, yet it is rare before the age of 50. The etiology of the condition remains unproven. Paget's disease of bone has become less common, less severe, and less extensive in recent decades. Isotope bone scans and radiographs remain the most frequent radiological investigations, demonstrating the extent of the disease and characteristic appearances in most cases. Recent changes in the radiological investigation of Paget's disease include increasing use of computed tomography (CT) and magnetic resonance (MR) imaging for the evaluation of less typical disease or disease complications; the incidental finding of Paget's disease on CT or MR requires recognition to avoid inappropriate investigation. The presence of sclerotic Paget's disease in the lumbar spine or hip may elevate bone mineral density measurements at these sites, with consequent potential to underestimate fracture risk. Awareness of the normal level-to-level vertebral variation in bone density in the spine, and careful assessment of the images acquired on dual energy X ray absorptiometry or quantitative CT will help to avoid this pitfall. Examples of these investigations and the combination of Paget's disease with other conditions such as osteoarthritis, metastatic bone disease, and bone infection are illustrated.