Journal of Clinical Medicine Article Amyloid Goiter in Familial Mediterranean Fever: Description of 42 Cases from a French Cohort and from Literature Review Hélène Vergneault 1 , Alexandre Terré 1, David Buob 2,†, Camille Buffet 3 , Anael Dumont 4, Samuel Ardois 5, Léa Savey 1, Agathe Pardon 6,‡, Pierre-Antoine Michel 7, Jean-Jacques Boffa 7,†, Gilles Grateau 1,† and Sophie Georgin-Lavialle 1,*,† 1 Internal Medicine Department and National Reference Center for Autoinflammatory Diseases and Inflammatory Amyloidosis (CEREMAIA), APHP, Tenon Hospital, Sorbonne University, 4 rue de la Chine, 75020 Paris, France; [email protected] (H.V.); [email protected] (A.T.); [email protected] (L.S.); [email protected] (G.G.) 2 Department of Pathology, APHP, Tenon Hospital, Sorbonne University, 4 rue de la Chine, 75020 Paris, France; [email protected] 3 Thyroid Pathologies and Endocrine Tumor Department, APHP, Pitié-Salpêtrière Hospital, Sorbonne University, 47-83 Boulevard de l’Hôpital, 75013 Paris, France; [email protected] 4 Department of Internal Medicine, Caen University Hospital, Avenue de la Côte de Nacre, 14000 Caen, France; [email protected] 5 Department of Internal Medecine, Rennes Medical University, 2 rue Henri le Guilloux, 35000 Rennes, France; [email protected] 6 Dialysis Center, CH Sud Francilien, 40 Avenue Serge Dassault, 91100 Corbeil-Essonnes, France; [email protected] 7 Citation: Vergneault, H.; Terré, A.; Department of Nephrology, APHP, Tenon Hospital, 4 rue de la Chine, 75020 Paris, France; [email protected] (P.-A.M.); [email protected] (J.-J.B.) Buob, D.; Buffet, C.; Dumont, A.; * Correspondence: [email protected]; Tel.: +33-156016077 Ardois, S.; Savey, L.; Pardon, A.; † Groupe de Recherche Clinique amylose AA Sorbonne Université- GRAASU. Michel, P.-A.; Boffa, J.-J.; et al. ‡ Groupe de Recherche Clinique n◦16 Tumeurs Thyroïdiennes. Amyloid Goiter in Familial Mediterranean Fever: Description of Abstract: Our aim was to describe the main features of amyloid goiter in adults with amyloidosis 42 Cases from a French Cohort and secondary to familial Mediterranean fever. Therefore, we analyzed cases from a French cohort from Literature Review. J. Clin. Med. 2021, 10, 1983. https://doi.org/ of familial Mediterranean fever patients with amyloidosis and from literature review. Forty-two 10.3390/jcm10091983 cases were identified: 9 from the French cohort and 33 from literature review. Ninety percent of patients were on hemodialysis for renal amyloidosis before the development of goiter. The Academic Editors: Isabelle Touïtou goiter grew up rapidly in 88% of cases; 75.6% of patients were euthyroid, 58% displayed dyspnea, and Jeroen van der Hilst and 44.8% dysphagia. Various features were seen on ultrasound, from diffuse to multinodular goiter. When it was performed, fine-needle aspiration biopsy almost always revealed amyloidosis. Received: 17 April 2021 Thirty-one patients underwent thyroidectomy: to manage compressive symptoms (72%) or rule Accepted: 2 May 2021 out malignancy (27%). Histology showed mature adipose tissue in 64% of cases and lymphocytic Published: 5 May 2021 infiltration in 21.4%. In conclusion, amyloid goiter in familial Mediterranean fever preferentially occurs in patients with end stage renal failure. Fine-needle aspiration biopsy seems to be a sensitive Publisher’s Note: MDPI stays neutral exam for diagnosis, but thyroidectomy remains sometimes necessary to rule out malignancy or with regard to jurisdictional claims in release compressive symptoms. published maps and institutional affil- iations. Keywords: familial Mediterranean fever; AA amyloidosis; goiter Copyright: © 2021 by the authors. 1. Introduction Licensee MDPI, Basel, Switzerland. This article is an open access article Familial Mediterranean fever (FMF) is the most frequent monogenic auto-inflammatory distributed under the terms and disorder that affects patients from the Mediterranean littoral [1]. This recessively inherited conditions of the Creative Commons condition is caused by mutations in MEFV gene mostly located in exon 10. Patients suffer Attribution (CC BY) license (https:// from episodic febrile attacks of abdominal or chest pain due to inflammation of serosal creativecommons.org/licenses/by/ tissues. These symptoms are accompanied by biological inflammatory markers elevation 4.0/). and can be prevent by a daily colchicine intake. AA amyloidosis is a severe complication J. Clin. Med. 2021, 10, 1983. https://doi.org/10.3390/jcm10091983 https://www.mdpi.com/journal/jcm J.J. Clin.Clin. Med. 2021,, 10,, 1983x FOR PEER REVIEW 22 of of 11 elevationof FMF. This and condition can be prevent is characterized by a daily colchicine by fibrillar intake. depositions AA amyloidosis of serum amyloid is a severe A (SAA) com- protein,plication especiallyof FMF. This in kidneyscondition [2 is], characterized due to chronic by inflammation fibrillar depositions and particularly of serum amyloid seen in patientsA (SAA) withprotein, an uncontrolled especially in disease.kidneys [2], due to chronic inflammation and particularly seen Thein patients term goiter with an refers uncontrolled to an abnormal disease. thyroid enlargement commonly due to auto- immuneThe term disease, goiter nodules, refers to or an iodine abnormal deficiency. thyroid Goiter enlargement can be commonly suspected due on physicalto auto- immuneexamination disease, and nodules is confirmed, or iodine by ultrasonographic deficiency. Goiter measurement can be suspected of gland on physical volume. exam- De- pendingination and on theis confirmed etiology,goiter by ultrasonographic can be diffuse or measurement nodular, and of thyroid gland hormonevolume. Depending production oncan the be etiology, normal, increased,goiter can orbe reduced. diffuse or nodular, and thyroid hormone production can be normal,Microscopic increased amyloid, or reduced. infiltration of the thyroid gland was first described by Rokitansky in 1855Microscopic [3] and according amyloid infiltration an autopsy of the cohort, thyroid it would gland was occur first in described about 59% by Rokitansky of patients insuffering 1855 [3] from and according AA amyloidosis an autopsy [4]. The cohort, term it of would amyloid occur goiter in about was first59% usedof patients by Eiselberg suffer- ingin 1904 from to AA describe amyloidosis the enlargement [4]. The term of of the amyloid gland goiter by amyloid was first deposits, used by whichEiselberg is farin 1904 less tofrequent describe [5 ].the enlargement of the gland by amyloid deposits, which is far less frequent [5]. Our aim waswas toto describedescribe the the main main features features of of amyloid amyloid goiter goiter in FMFin FMF patients patients with with AA amyloidosis through the French cases from the national reference center for FMF and AA AA amyloidosis through the French cases from the national reference center for FMF and amyloidosis and a literature review. AA amyloidosis and a literature review. 2. Materials and Methods 2. Materials and Methods A retrospective review of the 59 patients with AA amyloidosis secondary to FMF followedA retrospective in Tenon Hospitalreview of (Paris,the 59 patients France) with between AA amyloidosis January 1982 secondary and January to FMF 2020 followed was performed.in Tenon Hospital (Paris, France) between January 1982 and January 2020 was performed. For the literature review, a PUBMEB search was performed until August 2019 looking for case series or reports of of patients. The The following following search search was was done: done: « «amyloidamyloid goiter goiter», », «familial«familial Mediterranean fever AND amyloid goiter goiter» » andand «familial«familial MediterraneanMediterranean feverfever AND goiter».goiter ». ArticlesArticles whomwhom abstract or full-textfull-text if needed were not available were ex- cluded, as well as articles written in a language other than French or English,English, articles with no clinical details of goiter or or uncertain uncertain etiology, etiology, articles dealing with non non-AA-amyloidosis,-AA-amyloidosis, and articles dealing dealing with with amyloidosis amyloidosis secondary secondary to to an an etiology etiology other other than than FMF FMF (Figure (Figure 1).1). Figure 1.1. Flowchart. J. Clin. Med. 2021, 10, 1983 3 of 11 Patients were considered as having amyloid goiter if they had a visible and/or palpa- ble goiter or ultrasonographic enlargement (>18 cm3 in women, >20 cm3 in men) of the gland and histological or cytological exam of a thyroid sample showing positive Congo- red stained deposits with typical green-yellow birefringence. If no thyroid sample was available, the diagnosis of amyloid goiter was retained in patient with previous diagnosed AA amyloidosis if there was no evidence of alternative diagnosis, specifically: absence of auto-immune thyroiditis defined by the absence of antibodies anti-thyroid peroxidase, anti- thyroglobulin and anti-thyroid-stimulating hormone receptor (TSHR), lack of suspicion of malignant condition such as homogenous goiter, absence of nodule, and no evidence of drug-induced goiter. The following information were collected through a standard form: age at FMF diagnosis, age at amyloidosis and goiter diagnosis, kidney function, hemodialysis, thyroid function, goiter clinical features, histological characteristics, fine-needle aspiration biopsy (FNAB), and goiter management. Euthyroidism was defined by normal levels of TSH, T3, and T4, and subclinical hypothyroidism was defined