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Erdheim–Chester disease: Diagnosis in endocrinology
Enfermedad de Erdheim-Chester: diagnostico en endocrinología
María José Vallejo Herreraa,
Corresponding author
, Francisco José Sánchez Torralvoa, Verónica Vallejo Herrerab, Gabriel Olveira Fustera, Iván Pérez de Pedroc
a UGC Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, Málaga, Spain
b UGC Radiodiagnóstico, Hospital Regional Universitario de Málaga, Spain
c UGC Medicina Interna, Hospital Regional Universitario de Málaga, Spain
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previously reported by the patient&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Imaging tests and&#44; in particular&#44; bone biopsy were key to arriving at the diagnosis&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The patient was a 50-year-old man in follow-up by rheumatology for migratory arthralgia with bone scintigraphy showing diffuse radioactive tracer deposition in the long bones of the arms and legs&#44; consistent with osteosclerosis&#46; At an appointment in early 2019&#44; the patient reported that he drank around nine litres of water per day due to intense thirst&#44; whereupon he was referred for assessment by endocrinology&#46; The possibility of polydipsia was considered&#44; but ruled out following a dehydration test&#44; with results consistent with central diabetes insipidus and an excellent response to desmopressin&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The test results were&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Hormone tests</span>&#58; no other pituitary or gonadal deficiencies&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0035" class="elsevierStylePara elsevierViewall">Imaging tests&#58; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0040" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Computed tomography &#40;CT&#41; of the chest&#44; abdomen and pelvis</span>&#58; lung parenchyma featuring a ground-glass pattern with interstitial thickening in the right lower lobe consistent with an inflammatory process&#44; without any other findings of note&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Magnetic resonance imaging &#40;MRI&#41; of the brain</span>&#58; multiple small signal abnormalities on both sides of the midline of the brain stem and cerebellum&#46; No pathological abnormalities were seen in the pituitary gland&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Positron emission tomography&#47;computed tomography &#40;PET&#47;CT&#41;</span>&#58; diffuse involvement of bone marrow of long bones&#44; with greater uptake in the left proximal tibial metaphysis&#46; Hypermetabolic focus in left pons in relation to active lesion&#46; Increases in hypermetabolic density in right lung consistent with inflammatory signs which&#44; along with the hypermetabolic lymphadenopathy reported in the right paratracheal and subcarinal region&#44; were suggestive of an inflammatory process&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Bone biopsy of proximal tibial metaphysis</span>&#58; lesions suggestive of histiocytosis&#46; CD68&#43;&#44; CD1a and S100 negative&#46; Positive for BRAF V600E mutation&#46;</p></li></ul></p><p id="par0060" class="elsevierStylePara elsevierViewall">With the above findings&#44; the patient was diagnosed with ECD&#46; In this case&#44; the patient was referred to haematology to start treatment as mandated by the central nervous system involvement he exhibited&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">In adults&#44; the most common type of non-endocrine involvement in ECD is bone involvement&#44; in the form of metadiaphyseal osteosclerosis of the long bones &#40;80&#37;&#8211;95&#37; of patients&#41;&#44; which can cause bone pain or be asymptomatic&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Regarding endocrine manifestations&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleBold">diabetes insipidus</span> develops in a third of patients&#44; often as the first sign&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> Anterior hypopituitarism is found in the vast majority of patients when complete pituitary function is evaluated&#46; The following may appear&#44; in order of frequency&#58; growth hormone &#40;GH&#41; deficiency&#44; hyperprolactinaemia&#44; gonadotropin deficiency&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> thyrotropin deficiency and corticotropin deficiency&#46; On MRI&#44; infiltration of the pituitary gland with pituitary stalk thickening is found in 24&#37; of patients&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Testicular failure appears in half of patients&#44; with bilateral testicular infiltration on ultrasound&#46; Adrenal infiltration on CT is seen in a third of patients and may manifest as adrenal insufficiency&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Central nervous system involvement occurs in around 30&#37;&#8211;50&#37; of cases&#46; It sometimes leads to severe disability and constitutes the main factor in a poor prognosis&#46; Pyramidal and cerebellar syndromes are the earliest and most common neurological signs&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">One out of every four patients develops exophthalmos due to infiltration of retro-orbital tissue&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The most common cardiovascular sign is the coated aorta sign&#46; A wall mass due to infiltration&#8212;the so-called pseudotumour of the right atrium&#8212;may be observed&#46; It causes infiltration of the pericardium and coronary arteries with myocardial infarction&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In the retroperitoneal area&#44; abdominal CT reveals infiltration of perirenal fat&#44; with characteristic imaging of hairy kidneys in 60&#37; of patients&#46; One third have retroperitoneal fibrosis&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Skin manifestations consist of xanthelasma&#44; while lung involvement is seen in half of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;4</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Concerning molecular pathogenesis&#44; ECD is a clonal neoplastic disorder driven by mutations in the mitogen-activated protein kinase &#40;MAPK&#41; pathway &#40;RAS&#47;RAF&#47;MEK&#47;ERK&#41;&#44; which are targets of molecular therapy in histiocytosis&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">It is associated with myeloid leukaemia&#44; myelodysplastic syndrome&#44; other systemic histiocytoses and other autoimmune diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Arrival at a <span class="elsevierStyleBold">diagnosis</span> requires joint analysis of histopathological characteristics and clinical&#44; radiological and molecular findings&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Biopsy of affected tissues is required in all cases&#44; not only to confirm the diagnosis with identification of histiocytes featuring a characteristic immunohistochemistry pattern&#44; but also to enable identification of associated mutations for treatment purposes&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The most significant histopathological findings consist of infiltration by &#8220;foamy&#8221; histiocytes&#46; ECD can be distinguished from Langerhans&#39; cell histiocytosis by the immunohistological characteristics of its histiocytes&#44; which are positive for CD68 and negative for CD1a and CD207 &#40;which are characteristic of Langerhans&#39; cell histiocytosis&#41;&#46; Once the histological diagnosis is confirmed&#44; the BRAF V600E mutation is verified in all patients&#46; If negative&#44; abnormalities in other MAPK pathway genes should be investigated&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Radiological findings such as osteosclerosis&#44; infiltration of perirenal fat and proliferation of soft tissue surrounding the aorta are highly characteristic&#46; PET&#47;CT scans show pathological uptake that is useful for establishing the diagnosis&#44; guiding biopsies and assessing extent and treatment response&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Treatment decisions</span> are difficult to generalise and should be adapted to the characteristics of each individual patient and the seriousness&#44; location and extent of their lesions&#46; An expert consensus was published in 2014 &#40;Diamond et al&#46;&#41;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and updated in 2020 &#40;Goyal et al&#46;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Most patients will require treatment&#44; except those who have asymptomatic forms with involvement of a single non-vital organ &#40;bone&#41;&#46; Conventional treatments are available&#44; such as interferon&#44; with extensive experience in its use&#44; as well as interleukin-1 and interleukin-6 receptor antagonists&#46; Targeted treatments are also available&#44; with BRAF inhibitors such as vemurafenib&#44; MEK inhibitors such as cobimetinib or a combination of the two&#46; Other available treatments are mTOR inhibitors such as sirolimus and tyrosine kinase inhibitors&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">At present&#44; BRAF inhibitors are first-line drugs&#46; For BRAF V600 mutation-negative patients&#44; it is advisable to look for other MAPK pathway abnormalities&#44; which can be treated with a MEK inhibitor&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">In conclusion&#44; the first sign of central nervous system involvement due to ECD in our patient was diabetes insipidus&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The manifestation of prior skeletal signs as well as characteristic radiological and histological findings led to the patient&#39;s definitive diagnosis&#59; hence&#44; a comprehensive medical history by endocrinology was of particular importance in suspecting this rare disease&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Vallejo Herrera MJ&#44; S&#225;nchez Torralvo FJ&#44; Vallejo Herrera V&#44; Olveira Fuster G&#44; P&#233;rez de Pedro I&#46; Enfermedad de Erdheim-Chester&#58; diagnostico en endocrinolog&#237;a&#46; Endocrinol Diabetes Nutr&#46; 2022&#59;69&#58;444&#8211;446&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Radiological findings&#58; Characteristic bone involvement on PET&#47;CT and bone scintigraphy&#44; CT of the abdomen with no pathological findings in the kidney&#59; MRI of the brain&#46; Sagittal slices in T1 and axial slices enhanced in T2 FLAIR&#46; The sellar region shows no significant pathological abnormalities&#46; Multiple hyperintense signal abnormalities are identified on T2 FLAIR in the brain stem&#44; especially in the area of the pons&#46;</p>"
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Article information
ISSN: 25300180
Original language: English
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