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A 47-year-old male with a prior history of central diabetes insipidus (DI) presented with bone pain and ataxia.
He was initially referred to an endocrin-ologist in 1993 for evaluation of DI. It was concluded that he had lymphocytic infundibulitis based on the finding of a thickened pituitary stalk on MRI, while CSF examination revealed no evidence of infection or neoplastic disease. His symptoms of DI were controlled with DDAVP. He showed no other evidence of anterior pituitary hormone deficiencies. Although subsequent imaging showed resolution of the pituitary stalk thickening, his DI never resolved.
In 2012, he was admitted to the hospital for evaluation of lethargy, confusion, impaired short-term memory, and left lower extremity weakness. The altered mental status
was transient and resolved five days later. A brain MRI was initially interpreted as unremarkable. A few months later, he developed progressive gait instability, slurred speech, and impaired motor coordination. He could not fully perform his work duties and lost his job. His brain MRI was reexamined and showed evidence of significant cerebellar midline atrophy. On exam, he exhibited horizontal nystag-mus, dysarthria, gait impairment, and truncal ataxia greater than limb ataxia. The etiology was unclear.
He complained of chronic leg pain since 2005, which became progressively more severe. In 2018, osteosclerotic lesions were found on x-ray of his tibia, for which he underwent a bone biopsy with diagnosis of Paget’s disease (PD) at a community hospital. His calcium, phosphate, 25 hydroxy vitamin D, parathyroid hormone, and alkaline phosphatase were normal.
Subsequently, he was seen at UPMC for shoulder pain. X-rays noted lesions of the pedicle of the left shoulder and pelvis, medullary sclerosis in the humeral diaphysis (Figure 1), and symmetrical lesions in the distal femur and tibia bilaterally. Bone scan and FDG-PET scan showed increased activity in the lesions. A follow-up brain MRI revealed absence of the posterior pituitary bright spot, enhancement along the proximal 7th and 8th nerve complex, disproportionate cerebellar atrophy, and enhancement along the bilateral cerebellar folia that had progressed compared to the 2012 MRI. A repeat right tibial biopsy at UPMC revealed marrow infiltration with histiocytes (some were lipid laden), fibrosis, and sclerosis of trabecular bone. The histiocytes were highlighted by CD163, CD68, CD14, factor XIIIa, and fascin. A few scattered histiocytes were BRAF V600E immunostain positive. The findings were consistent with a diagnosis of Erdheim-Chester disease (ECD). He will be treated with vemurafenib.
We report a rare case of non-Langerhans cell histiocytosis originally described by Jakob Erdheim and William Chester in 1930.1 ECD is a rare type of hematopoietic neoplasm that is characterized by abnormal proliferation and infiltration of CD68-positive, CD1a-/S100-negative foamy histiocytes causing xanthogranulomatous inflammation in multiple organs. It is not genetically inherited. Its incidence is unknown, but ~500 cases have been reported in the literature. Although described in all age groups, it is most common in adults with a mean age at diagnosis of 53 years, with a slight male predominance. The discovery of BRAF V600E mutation encountered in 50 percent of cases is proof of an oncogenic process in this disorder.2 Mutations at V600E result in increased kinase activity that enhances cell proliferation and survival by activating the RAS/RAF/MEK/MAPK signaling pathway. Additional mutations in NRAS (Q61R), KRAS, ARAF, PIK3CA, and MAP2K1 have been associated with ECD.3
This disease can affect any organ system, but the most common clinical manifestation is multifocal cortical osteosclerotic lesions of the diaphyseal and metaphyseal part of long bones (95 percent). Pituitary/orbit (22 percent), central nervous system (41 percent), pulmonary (46 percent), and cardiovascular (57 percent) involvement have been reported.4 DI is a feature that occurs early in the disease process in ~25 percent of patients. The involvement of the pituitary commonly causes central DI, but it also can cause anterior pituitary hormone deficiencies and hyperprolactinemia.5 Even when there is clear evidence of radiographic regression of the pituitary disease, the endocrinopathy usually persists, as in our patient.6
The differential diagnosis of ECD is broad and includes Langerhans cell histiocytosis, Wegener’s granulomatosis, PD, neurosar-coidosis, mycobacterial disease, and more.7 This patient’s bone lesions were initially misdiagnosed as PD, but a repeat bone biopsy with immunostain for BRAF V600E provided his correct diagnosis. The diagnosis is best made on histopathologic evaluation of involved tissue (bone preferred) along with genetic testing or immunostaining of the tissue for BRAF V600E. The bone abnormalities seen in ECD are characterized by osteosclerotic lesions, which also are a feature in PD. In contrast to PD, the bone lesions in ECD are bilateral and symmetric, and affect the diaphysis of the long bones specifically.8 MRI of the brain, cardiac MRI, bone scan, and PET/CT of chest, abdomen, pelvis, and distal extremities are recommended for staging in patients with ECD.9
The clinical course of ECD is variable, and some patients can be asymptomatic for decades. Treatment is not necessary for patients who are asymptomatic and have no evidence of central nervous system involvement or any organ dysfunction. If symptomatic and without the BRAF V600E mutation, treatment with interferon alpha can improve survival. Glucocorticoids have been shown to have some clinical efficacy but provide no survival benefit.10 For symptomatic patients who are positive for BRAF V600E, such as our patient, the initial recommended treatment is with the BRAF inhibitor, vemurafenib, which was recently approved by the FDA for these patients.11-13 Surgical debulking of large masses and radiation therapy for palliation of bone pain can also be employed as management options.
In summary, we report an unusual case of a young male who initially presented with central DI associated with thickening of the pituitary stalk on MRI, and a presumed diagnosis of lymphocytic infundibulitis. More than 10 years later, he developed ataxia, bone pain, and multifocal osteo-sclerotic bone lesions. The bone lesions were initially misdiagnosed as PD, but a repeat bone biopsy led to the correct diagnosis of ECD, a multisystem hema-topoietic neoplasm. His diagnosis was challenging due to the fact that ECD is rare and has features that overlap with other more common medical conditions.
1 Chester W. Lipoid Granulomatose. Virchows Arch Pathol Anat. 1930; 279 (2): 561–602.
2 Haroche J, Charlotte F, Arnaud L, at al. High Prevalence of BRAF V600E Mutations in Erdheim-Chester Disease But Not in Other non-Langerhans Cell Histiocytoses. Blood. 2012; 120(13): 2700-2703.
3 Campochiaro C, Tomelleri A, Cavalli G, Berti A, Dagna L. Erdheim-Chester Disease. Eur J Intern Med. 2015 May; 26(4): 223-9.
4 Cives M, Simone V, Rizzo FM, Dicuonzo F, Cristallo Lacalamita M, Ingravallo G, Silvestris F, Dammacco F. Erdheim-Chester Disease: A Systematic Review. Crit Rev Oncol Hematol. 2015 Jul; 95(1): 1-11.
5 Haroche J, Arnaud L, Cohen-Aubart F, et al. Erdheim-Chester Disease. Rheum Dis Clin North Am. 2013; 39(2): 299-311.
6 Cavalli G, Guglielmi B, Berti A, et al. The Multi - faceted Clinical Presentations and Manifestations of Erdheim-Chester Disease: Comprehensive Review of the Literature and of 10 New Cases. Ann Rheum Dis. 2013; 72: 1691.
7 Alotaibi S, Alhaifi O, Nasr H, et al. Erdheim-Chester Disease: Case Report With Aggressive Multisystem Manifestations and Review of the Literature. Case Rep Oncol. 2017; 10: 501-507.
8 Dagna L, Girlanda S, Langheim S, at al. Erdheim-Chester Disease: Report on a Case and New Insights on Its Immunopathogenesis. Rheumatology (Oxford). 2010; 49: 1203.
9 Diamond EL, Dagna L, Hyman DM, Cavalli G, Janku F, et al. Consensus Guidelines for the Diagnosis and Clinical Management of Erdheim-Chester Disease. Blood. 2014 Jul 24; 124(4): 483-92.
10 Arnaud L, Hervier B, Neel A, Hamidou MA, Kahn JE, Wechsler B, Perez-Pastor G, Blomberg B, Fuzibet JG, Dubourguet F, et al. CNS Involvement and Treatment With Interferon-alpha Are Independent Prognostic Factors in Erdheim-Chester Disease: A Multicenter Survival Analysis of 53 Patients. Blood. 2011; 117: 2778–2782.
12 Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in Multiple Nonmelanoma Cancers With BRAF V600 Mutations. N Engl J Med. 2015; 373: 726.
Mihaela Oprea, MD
Division of Endocrinology and Metabolism
Sue M. Challinor, MD
Professor of Medicine
Division of Endocrinology and Metabolism