ReviewClinical and genetic characterization of the autoinflammatory diseases diagnosed in an adult reference center☆
Introduction
The term autoinflammatory diseases (AID) was first delineated in 1999 to encompass a group of disorders of the innate immune system characterized by recurrent episodes of inflammation without a known trigger [1]. The most frequent AID share a genetic background and are caused by mutations in genes encoding proteins directly involved in the biology of inflammasome, in which interleukin-1 (IL-1), a proinflammatory cytokine and important mediator of the systemic inflammatory response, plays a crucial role. In contrast to autoimmune diseases, no high titer autoantibodies or specific-T or B-cell autoreactivity are detected in AID [2], [3], [4]. Although AID are considered dominant or recessive inherited diseases with a Mendelian inheritance pattern, in some conditions genetic variants have been described as “de novo” mutations in almost 50% of patients [5].
The most common AID in the Mediterranean area include familial Mediterranean fever (FMF), tumour necrosis factor (TNF)-receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD)/hyper-immunoglobulin D (IgD) syndrome and periodic fever (HIDS), the family of cryopyrin associated periodic syndromes (CAPS) [familial cold induced autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and chronic infantile neurologic, cutaneous and articular syndrome (CINCA)] and periodic fever, aphtous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. All of them have a monogenic origin [4], with the exception of PFAPA syndrome, in which the underlying etiology is still unknown [6], [7].
The diagnostic process of AID is often difficult since awareness for these rare and relatively new diseases is still low for general practitioners. In an appropriate clinical setting, a positive genetic study usually provides a definite diagnosis. On the other hand, although monogenic AID and PFAPA syndrome are usually diagnosed during childhood, all of them may have an adult onset [8], [9], [10], [11], [12]. In addition, many of these syndromes present with overlapping manifestations, frequently shared with other autoinflammatory conditions, which can usually make the diagnostic process even more difficult.
AID diagnosis may be reached during adulthood in patients with a clinical onset in adult life and in those in whom symptoms started during the infancy but were probably misinterpreted by physicians over the years. In this regard, investigations of AID in adults are still scarce. However, several studies have reported clinical and genetic differences between patients with a disease-onset during adulthood and those with pediatric onset [9], [10], [11], [12].
In the present study, we retrospectively reviewed clinical and genetic features of patients diagnosed with an AID in an adult reference center for AID or referred for treatment and control. We also compared our results with those reported in the literature from other studies about AID in pediatric age.
Section snippets
Patients' selection and data collection
From January 2008 to March 2014, all adult patients in whom AID were suspected and a genetic test for a known AID was requested at the Department of Autoimmune Diseases of the Hospital Clínic of Barcelona were included in the study. Patients transferred from other adult departments to our unit after a confirmative diagnosis of AID were also analyzed.
All monogenic AID patients were diagnosed by the presence of suggestive clinical features, genetic confirmation and response to
Results
From 2008 to 2014, 90 genetic tests were requested at the Department of Autoimmune Diseases of the Hospital Clínic of Barcelona for a suspected AID. A final diagnosis of a monogenic AID (FMF, TRAPS, CAPS and MKD/HIDS) was achieved in 17 (19%) patients. With the addition of 5 patients diagnosed with PFAPA, 22 patients were diagnosed with an AID, which accounts for 24.4% of the patients screened for AID. Ten patients diagnosed with AID were also referred to our Clinical Unit of AID from other
Discussion
AID are inherited conditions typically occurring in pediatric age. Their diagnosis usually presents a challenge, often more complex when they occur in adult patients. To date, the detection rate of mutations in patients with high suspicion for AID is low, accounting for less than 20% in most pediatric series [9], [24]. Of note, we found a similar rate of positive genetic tests in adult patients with an initially suspected AID. With the aim of improving genetic diagnosis in adults with suspected
Conclusions
AID, although infrequently, may have an adult-onset. Our results support that adult patients diagnosed with AID may develop disease-related symptoms during the adult age or have a delayed diagnosis of symptoms starting during infancy. These patients usually present with mild forms of the disease leading to a remarkable diagnostic delay until adulthood. Some of them may also present with atypical manifestations that are frequently shared by other AID, which might be classified as overlap
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Supported by the Excellence Integrated Project co-funded by Instituto de Salud Carlos III and FEDER (PIE 13/00033) and Ministerio de Economía y Competitividad (SAF 14/57708-R).