1 Autoinflammatory Diseases in 2 3 4 Pediatrics 5 Q2Q3 Jonathan S. Hausmann, MD*, Fatma Dedeoglu, MD Q4 6 7 KEYWORDS 8 Autoinflammatory diseases Periodic fever Pediatrics Familial Mediterranean fever PFAPA 9 HIDS TRAPS CAPS 10 11 12 KEY POINTS 55 13 56 Viral infections are the most common cause of recurrent fevers in children. 14 57 Autoinflammatory diseases (AIDs) should be considered in a child with recurrent or persistent fever, 15 58 when infectious and malignant causes have been excluded. 16 59 17 AIDs are characterized by recurrent episodes of systemic and organ-specific inflammation, and are 60 18 caused by defects in the innate immune system. 61 19 Periodic fevers with aphthous stomatitis, pharyngitis, and cervical adenitis is the most common AID 62 20 in children and occurs at regular intervals. 63 21 Familial Mediterranean fever is the most common monogenic AID and presents with recurrent 64 22 attacks of fever, abdominal pain, arthritis, and rash that last for 1 to 3 days. 65 23 66 24 67 25 68 26 69 27 Q6 INTRODUCTION inborn errors of the innate immune system.1 They 70 28 involve disorders of neutrophils, macrophages, 71 Repeated febrile illnesses are common in young 29 and molecules of innate immunity that evolved to 72 children, especially in those attending daycare 30 protect against external pathogens. These innate 73 and school. Most often, these febrile episodes are 31 immune cells are activated by endogenous or 74 caused by repeated viral infections. However, if 32 exogenous stimuli, so-called pathogen-associated 75 there is continued recurrence of fever and other 33 molecular patterns (PAMPs) and damage- 76 associated symptoms, it is important to maintain a 34 associated molecular patterns (DAMPs), which 77 broad differential that includes primary immuno- 35 lead to inflammation. 78 deficiencies, anatomic and metabolic abnormali- 36 In contrast with most autoimmune diseases, 79 ties, malignancies, and autoinflammatory diseases 37 AIDs usually present during childhood. Many are 80 (AIDs). The diagnosis of an AID may be challenging, 38 characterized by recurrent or persistent fever, 81 because there are numerous diseases, overlapping 39 and they are an important part of the differential 82 signs and symptoms, and lack of specific laboratory 40 diagnosis of the febrile child. It is essential for phy- 83 testing. 41 sicians who care for children to recognize these 84 AIDs are characterized by recurrent episodes of 42 disorders, and to refer these children to specialists 85 systemic and organ-specific inflammation. Unlike 43 who can initiate treatment, improve quality of life, 86 patients with autoimmune disorders such as sys- 44 and avoid long-term complications. temic lupus erythematosus, patients with AIDs 45 Research over the last 10 years has identified do not have the presence of autoantibodies or 46 many of the genes that cause AIDs. Most of these antigen-specific T cells. Instead, AIDs result from 47 diseases are monogenic and inherited in an 48 49 50 51 No disclosures. 52 Program in Rheumatology, Division of Immunology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA Q5 53 * Corresponding author. 54 E-mail address: [email protected] Dermatol Clin - (2013) -–- http://dx.doi.org/10.1016/j.det.2013.04.003 0733-8635/13/$ – see front matter Ó 2013 Published by Elsevier Inc. derm.theclinics.com DET818_proof ■ 3 May 2013 ■ 10:58 am 2 Hausmann & Dedeoglu 87 autosomal dominant or recessive pattern. How- infections should be evaluated for immunodefi- 144 88 ever, understanding of these diseases continues ciencies, cystic fibrosis, or anatomic abnormal- 145 89 to evolve. Most children with periodic fevers ities. Parasitic infections with Plasmodium may 146 90 (greater than 80% in some studies) do not have mu- occur in children who have traveled to endemic 147 91 tations in known periodic fever syndrome genes.2 areas. 148 92 This article presents the differential diagnosis of Inflammatory bowel disease is a common cause 149 93 recurrent fever in children. It discusses periodic of recurrent fevers, and the fevers may precede 150 94 fevers with aphthous stomatitis, pharyngitis, and other signs of inflammatory bowel disease, such 151 95 cervical adenitis (PFAPA), the most common AID as abdominal pain, bloody stools, poor growth, 152 96 in children. It then focuses on the clinical presenta- and anemia, by weeks or months. 153 97 tion of monogenic AIDs that present with fevers In Behc¸ et disease, children also present with 154 98 in children, including familial Mediterranean fever recurrent oral and genital ulcers, uveitis, or skin 155 99 (FMF), tumor necrosis factor (TNF) receptor–asso- rashes such as erythema nodosum. Systemic ju- 156 100 ciated periodic syndrome (TRAPS), cryopyrin- venile idiopathic arthritis presents with at least 157 101 associated periodic syndromes (CAPS), deficiency 2 weeks of daily fevers, along with a rash, lymph- 158 102 of interleukin-36 receptor antagonist (DITRA), adenopathy, hepatosplenomegaly, or serositis. 159 103 Majeed syndrome, and chronic atypical neutro- These two syndromes share many of the features 160 104 philic dermatosis with lipodystrophy and increased of AIDs but no clear genetic causes have been 161 105 temperature syndrome (CANDLE). Two granulo- identified. 162 106 matous disorders, pyogenic sterile arthritis, pyo- After the diagnoses mentioned earlier have been 163 107 derma gangrenosum, and acne (PAPA) syndrome evaluated, AIDs should be considered, especially 164 108 and Blau syndrome, are also discussed. if there is a family history of recurrent fevers or if 165 109 the child is of certain ethnic groups. One of the 166 110 167 RECURRENT FEVERS characteristics of AIDs is that the fever pattern 111 and associated features are similar between epi- 168 112 Fever is one of the most common reasons for chil- sodes. In most of these diseases, children are 169 113 dren to visit their pediatrician.3 Some children pre- well between episodes, although some of them 170 114 sent with recurrent or periodic fevers, defined as 3 follow a more chronic course and cause significant 171 115 or more episodes of fever in a 6-month period morbidity and mortality unless treated. Fever is not 172 116 without a known illness to explain the fevers, and a part of all of the AIDs, although this article 173 117 with at least 7 days between febrile episodes.4 focuses on the ones in which fever is present, 174 118 The approach to children with recurrent fevers and briefly touch on several without fevers. 175 119 should be different than that for children present- Clinical scoring systems have been created 176 120 ing with fever of unknown origin, because their to determine the likelihood that a child will have 177 121 causes may differ. an AID with a known genetic cause, and may 178 122 To better create a differential diagnosis, the help guide genetic testing (http://www.printo.it/ 179 123 pattern of the fevers should be characterized pre- periodicfever), although this needs to be validated 180 124 cisely, especially whether there is a regularity to in a diverse patient population. 181 125 the intervals of fever. Episodes of fever occurring 182 126 at regular intervals suggest a diagnosis of PFAPA PFAPA 183 127 or cyclic neutropenia. Other characteristics that 184 128 should be noted include the age of fever onset, The syndrome of PFAPA is the most common 185 129 cause of periodic fevers in childhood. First des- 186 height of the fever, and pattern during the day. 5 130 It is important to monitor for associated symp- cribed in 1987, it is characterized by recurrent 187 131 toms during an episode, including rashes, and febrile episodes lasting 3 to 6 days, occurring 188 132 involvement of the mucosa, joints, eyes, lung, or every 3 to 6 weeks, in addition to the presence 189 133 abdomen. of the features that make up the name of this syn- 190 134 Viral infections are the most common causes of drome. Regular intervals (with almost clockwork 191 135 fevers occurring at irregular intervals in children.4 regularity) between episodes are the cardinal 192 136 Although most viral infections cause obvious feature of PFAPA, whereas the presence of asso- 193 137 ciated symptoms is more varied. The disease is 194 symptoms, such as those of upper or lower respi- 6 138 ratory tract infections, many viruses can also common in most ethnic groups. 195 139 cause fevers without any other defining signs or 196 Cause 140 symptoms. 197 141 Most children with occult bacterial infections The cause of PFAPA is unknown. Genetic studies 198 142 present with prolonged rather than recurrent fe- have failed to find a common genetic abnormality 199 143 vers. However, children with repeated bacterial in patients with this syndrome. However, 17% to 200 DET818_proof ■ 3 May 2013 ■ 10:58 am Autoinflammatory Diseases in Pediatrics Q1 3 201 45% of children with PFAPA have a family history aphthae (<1 cm or less) or less frequently by a 258 202 of recurrent fevers, and 12% have a family history crop of small aphthae. 259 203 of PFAPA,7,8 suggesting a genetic susceptibility. Associated symptoms may include chills, head- 260 204 Some of these patients have been shown to have ache, nausea, diarrhea, abdominal pain, lethargy, 261 205 heterozygous mutations in various genes known poor appetite, myalgias, and arthralgias.10,13 Pa- 262 206 to be involved in other monogenic AIDs such as tients are completely well between episodes and 263 207 NRLP3, Mediterranean fever (MEFV), TNFRSF1a,