*Review* **Syndrome of Undifferentiated Recurrent Fever (SURF): An Emerging Group of Autoinflammatory Recurrent Fevers**

**Riccardo Papa, Federica Penco, Stefano Volpi, Diana Sutera, Roberta Caorsi and Marco Gattorno \***

Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; riccardopapa@gaslini.org (R.P.); federicapenco@gaslini.org (F.P.); stefanovolpi@gaslini.org (S.V.); dianasutera@icloud.com (D.S.); robertacaorsi@gaslini.org (R.C.)

**\*** Correspondence: marcogattorno@gaslini.org; Tel.: +39-0105-6361

**Abstract:** Syndrome of undifferentiated recurrent fever (SURF) is a heterogeneous group of autoinflammatory diseases (AID) characterized by self-limiting episodes of systemic inflammation without a confirmed molecular diagnosis, not fulfilling the criteria for periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome. In this review, we focused on the studies enrolling patients suspected of AID and genotyped them with next generation sequencing technologies in order to describe the clinical manifestations and treatment response of published cohorts of patients with SURF. We also propose a preliminary set of indications for the clinical suspicion of SURF that could help in everyday clinical practice.

**Keywords:** autoinflammatory diseases; NGS; SURF; FMF; colchicine; anakinra

Sutera, D.; Caorsi, R.; Gattorno, M. Syndrome of Undifferentiated Recurrent Fever (SURF): An Emerging Group of

Autoinflammatory Recurrent Fevers. *J. Clin. Med.* **2021**, *10*, 1963. https:// doi.org/10.3390/jcm10091963 Academic Editor: Eugen Feist Received: 28 February 2021 Accepted: 28 April 2021 Published: 3 May 2021

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iations.

4.0/).

**Citation:** Papa, R.; Penco, F.; Volpi, S.; **1. Introduction**

> Syndrome of undifferentiated recurrent fever (SURF) is a heterogeneous group of autoinflammatory diseases (AID) characterized by self-limiting episodes of systemic inflammation without a confirmed molecular diagnosis. First defined by Broderick et al., [1] SURF is increasingly diagnosed in patients with recurrent fever after exclusion of the main hereditary recurrent fevers (HRF) and periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome [2]. Recent evidence suggests the presence of a multi-organ presentation in SURF and, in a relevant percentage of the patients, a complete or at least partial response to colchicine, usually not observed with the same high frequency in PFAPA syndrome [3]. It is possible that omics-based technologies will provide a relevant opportunity to analyse the functional characteristics of immune cells in SURF patients, highlighting the pathological relevance of possible novel genes and supporting the development of new diagnostic tests. On the other hand, the response to colchicine suggests a possible crucial role of cytoskeleton and related proteins, as observed in the other form of HRF responding to this drug, namely the familial Mediterranean fever (FMF) [4]. In this systematic literature review, we will (1) identify a subgroup of patients with SURF among cohorts of patients with suspected AID undergoing next generation sequencing (NGS); (2) describe the clinical manifestations and therapeutic responses of these patients; (3) propose a set of indications for the clinical suspicion of SURF, with the aim of supporting the diagnostic approach in everyday life.
