Bilateral Nephroblastic Tumors and a Complex Renal Vascular Anomaly in a Patient With a Mosaic RASopathy: Novel Histopathologic Features and Molecular Insights

Mosaic RASopathies are an emerging group of disorders characterized by mosaic or post-zygotic activating mutations in genes of the RAS/MAPKinase signaling pathway. The phenotype is highly variable, ranging from limited or localized forms to cases with a syndromic presentation with extensive or multiorgan involvement, and also overlaps with other mosaic disorders. While there are several reports of malignancies in patients with mosaic RASopathies, specifically rhabdomyosarcoma and transitional urothelial carcinoma, the lifetime risk and molecular mechanisms that lead to the development of malignancies remain unclear. We report a 22-month-old boy with a somatic RASopathy due to an underlying KRAS p.G12D mutation who presented with a large unilateral epidermal nevus, asymmetric lower limb overgrowth with lytic and sclerotic bone lesions, capillary malformation, bilateral nephrogenic rests and Wilms tumors, and a novel complex renal vascular anomaly that resembles Fibro-Adipose Vascular Anomaly (FAVA). This report further expands the phenotypic spectrum of somatic RASopathies, and discusses the potential phenotypic and pathogenetic overlap with PIK3CA-related overgrowth disorders, specifically CLOVES. The occurrence of a secondary cancer hotspot mutation ( FBXW7 p.R479G ) in the Wilms tumor, but not the associated nephrogenic rest, moreover suggests that additional driver mutations are involved in the development of Wilms tumor in somatic overgrowth disorders.

Enostosis-related epilepsy

Unexpected bone lesions of the skull present a common dilemma, where radiological appearance and patient’s clinical background are crucial to avoid misdiagnosis. Enostosis are benign sclerotic bone lesions; its aetiology is still unknown and its management is usually conservative, with good prognosis. Most of these lesions are asymptomatic and neurological involvement is rare. We present the first report of enostosis-related epilepsy.

False-Positive 18F-FDG PET/CT Uptake in Unilateral Lactation

A 31-year-old woman (7 months postpartum and lactating) with multiple sclerotic bone lesions was referred for an 18F-FDG PET/CT scan for characterization. The scan demonstrated unilateral diffuse intense FDG uptake corresponding to dense soft tissue in the right breast, likely related to secretory hyperplasia. On further questioning, it was made apparent that she had only been breastfeeding from the right breast. While the left breast also demonstrated dense soft tissue to a lesser degree, no significant FDG uptake was seen. The sclerotic bone lesions were not FDG avid, likely due to a separate non-FDG avid benign condition or bony metastases from a non-FDG avid primary malignancy. This was reinforced by the fact that subsequent investigations including serial bilateral breast ultrasound and percutaneous biopsy demonstrated no definite evidence of malignancy in the bilateral breasts. The histopathology findings of an open surgical biopsy of sclerotic lesions in the left posterior ilium were also nonspecific, favouring bone dysplasia with no evidence of malignancy.

P37 Erdheim-Chester disease: an ultra-rare mimic of IgG4-related disease

Background A 56 year old female was hospitalised in July 2019 with abdominal pain and significant weight loss, but little in the way of bone pain. Examination showed no evidence of xanthelasma. A large pericardial effusion was detected, requiring pericardiocentesis. The pericardial fluid contained numerous macrophages staining with CD68. Methods CT scans were reported as consistent with metastatic carcinoma. There were multiple sclerotic bone lesions in the manubrium, T7, T11, L2 and L4. She also had a periaortitis with soft tissue infiltrate around the ascending aorta and aortic arch, in the mediastinum, posterior paravertebral region, and in the retroperitoneum, obscuring both adrenal glands and surrounding both kidneys. Bone marrow aspirate and trephine demonstrated reactive appearances only. Results She required re-admission with breathlessness due to recurrence of the pericardial effusion. Biopsy from the left perinephric region was performed. Histopathology revealed a fibroinflammatory disorder. Some histiocytes were seen. There was no evidence of the typical features of IgG4-RD such as storiform fibrosis or obliterative phlebitis, which had been the working diagnosis thus far. Serum IgG4 level was normal. The classical histological features of Erdheim-Chester disease (ECD, an ultra-rare non-Langerhans cell Histiocytosis) in terms of foamy macrophages and Touton cells, were not obvious, but in the literature, it is not uncommon for the typical histological appearances of ECD to be absent. Further investigation demonstrated the classical radiographic findings of ECD with symmetrical sclerotic lesions in the long bones of the lower limbs. Radionuclide bone scan showed multifocal symmetrical increase in isotope uptake, predominately in the distal femora, proximal and distal tibiae, mandible and maxillae with multiple lesions in the thoracic and lumbar spine. Endocrine failure is frequently seen in ECD. Fortunately, our patient had neither pituitary disease nor hypoadrenalism. Furthermore, CNS involvement, ataxia and retro-orbital disease have all been reported in ECD. Our patient has experienced daily episodes of right retro-orbital pain, dizziness on upward gaze without diplopia, and occasional staggering. An MRI of brain, orbits and whole spine is scheduled, as are a whole body FDG-PET scan and cardiac MRI (to exclude myocardial infiltration). BRAF V600E mutation analysis is in progress since around 50% of ECD patients with this mutation may respond to vemurafenib treatment. Conclusion In this illustrative case, the combination of a fibroinflammatory disorder surrounding both kidneys, along with recurrent pericardial effusion and sclerotic bone lesions, was clinically and radiologically diagnostic of Erdheim-Chester disease. ECD is a recognised mimic of IgG4-RD, which itself is a mimic of multiple other conditions, including metastatic carcinoma. We present this case to highlight this little-known condition. Rheumatologists and Physicians should consider ECD in the differential diagnosis of IgG4-RD, periaortitis, pericardial effusion, symmetrical sclerotic bone lesions, endocrine failure and neurological features. Disclosures J.S. McLaren None. V. Campbell None. M. Rahilly None. J.M. Rehman None. R. Cargill None.

An Atypical Case of POEMS Syndrome Associated with Autonomic Dysfunction

A 52 year old patient showed, for two years, symptoms compatible with sensorimotor polyneuropathy preventing him from walking. An electroneuromyography found a demyelinating pattern suggesting Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). The patient did not respond to corticosteroid therapy and later suffered sexual Dysfunction, Swelling, Lymphadenopathy, Hypotension, astrointestinal dysmotility, urinary retention and neuropathic pain. Analysis of the Cerebrospinal Fluid (CSF) revealed elevated protein levels and Computed Tomography (CT) scan found sclerotic bone lesions. High Vascular Endothelial Growth Factor (VEGF) levels and the results of Lambda light-Chain monoclonal gammopathy in urine protein Electrophoresis Suggested a Diagnosis of POEMS syndrome. The most striking feature, in this case, was the patient’s heightened and atypical polyneuropathy without axonal injury even after an extended period of time, and significant and atypical dysautonomia.

Multisystemic sarcoidosis—important lessons learnt from one of the great imitators

We report a case of a woman who was admitted with a suspicion of metastatic malignancy of unknown primary origin. A few months prior to her admission, she presented to a rheumatologist with acute anterior uveitis, psoriasiform rashes and polyarthritis. A diagnosis of psoriatic arthropathy was made and she was treated accordingly. Soon after she presented with persistent back and right upper quadrant abdominal pain for which she had a CT scan done with evidence of hilar lymphadenopathy, liver hypodensities and lytic-sclerotic bone lesions. She was referred to our hospital for further investigations and management. After re-exploring her clinical presentation and further investigations (including a liver biopsy), a diagnosis of multisystemic sarcoidosis with ocular, reticuloendothelial, hepatic and skeletal involvement was made. The patient was started on systemic glucocorticoids and second line immunosuppressants and demonstrated significant clinical improvement with resolution of her liver granulomata on imaging and improvement in her back pain. The case illustrates the importance of a thorough clinical assessment, review of investigations and an open mind in the evaluation of a patient.