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Year : 2018  |  Volume : 19  |  Issue : 3  |  Page : 194-201

Monogenic autoinflammatory syndromes in children: Through the dermatologist's lens

Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication28-Jun-2018

Correspondence Address:
Dr. Vishal Gupta
Department of Dermatology and Venereology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpd.IJPD_9_18

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Autoinflammatory syndromes are a group of rare disorders of innate immunity characterized by repeated episodes of inflammation without an obvious cause. Many of these disorders have a childhood onset, and present as recurrent fevers, skin lesions, joint pains and other systemic features. Newer autoinflammatory syndromes with previously undescribed clinical phenotypes are being increasingly recognized. Several of these have distinctive cutaneous manifestations, and dermatologists have an important role to play in the diagnosis of these conditions. Recently, molecular basis for many of these diseases has been identified, thus paving the way for novel targeted therapies. Interleukin-1 blockers have been found to be more effective than the conventional immunosuppressants in their treatment. In this article, we focus on the cutaneous features of well-recognized as well as some of the recently described monogenic autoinflammatory syndromes in children.

Keywords: Autoinflammatory syndromes, children, dermatological manifestations, skin

How to cite this article:
Gupta V, Ramam M. Monogenic autoinflammatory syndromes in children: Through the dermatologist's lens. Indian J Paediatr Dermatol 2018;19:194-201

How to cite this URL:
Gupta V, Ramam M. Monogenic autoinflammatory syndromes in children: Through the dermatologist's lens. Indian J Paediatr Dermatol [serial online] 2018 [cited 2020 Oct 29];19:194-201. Available from: https://www.ijpd.in/text.asp?2018/19/3/194/235498

  Introduction Top

Autoinflammatory syndromes are a set of clinically distinct disorders characterized by repeated episodes of inflammation, manifesting as recurrent fever, mucocutaneous lesions, serositis and osteoarticular symptoms. Although probably known since ancient times, our understanding of these disorders has increased only during the last few decades. The seemingly unprovoked episodes of inflammation are caused by a dysregulated innate immune system, which leads to excessive production of pro-inflammatory cytokines like interleukin (IL)-1 β.[1],[2] As the clinical manifestations of these diseases are being better characterized, importance of cutaneous features as a diagnostic clue is also being recognized. While many of these rare disorders are inherited, some common acquired diseases such as vitiligo, Behcet's disease, juvenile idiopathic arthritis, gout, and type II diabetes mellitus are also said to have an element of autoinflammation. In this review, our focus is on the monogenic autoinflammatory syndromes in children with prominent cutaneous manifestations.

  Inflammasomes and Autoinflammation Top

Inflammasomes belong to the family of pattern recognition receptors and are an integral part of the innate immune system. These multiprotein complexes can sense not only pathogen-associated molecular patterns but also intracellular molecules released from injured host cells. Activation of inflammasomes produces an inflammatory response by activating caspase, which in turn results in cleavage of inactive pro-IL-1 β to active IL-1 β. Caspase activation also leads to pyroptosis, a specific form of programmed cell death, which also releases pro-inflammatory molecules and further potentiates the inflammatory cascade.[3],[4] Activating mutations in genes coding for any component of the inflammasome pathway can lead to its constitutive activation, producing inflammation in the absence of a trigger. In fact, inflammasomes are so critical to the pathogenesis of autoinflammatory syndromes that these are also referred to as inflammasomopathies.[1]

  When to Suspect Autoinflammatory Syndrome? Top

There is no one clinical symptom, but rather a set of symptoms occurring repeatedly which suggests the diagnosis of autoinflammatory syndrome. The clinical features are often usually predictable during every episode and include a varying combination of fever, skin eruption, serositis and joint pains. It is important to exclude infections, connective tissue diseases and malignancies as a cause of recurrent fever before seriously considering the possibility of an autoinflammatory syndrome. Further, there is often a delay in recognizing that the clinical features follow a pattern. With the extending clinical spectrum of autoinflammatory syndromes, we now know that some of these may have continuous fever or no fever at all. Other clues include childhood onset, positive family history and raised laboratory markers of systemic inflammation during the episodes.[1],[5]

As skin lesions are often the leading symptoms, a dermatologist's opinion is sought frequently. Many autoinflammatory syndromes present with an urticarial rash, the so-called “atypical urticaria.” From the dermatologist's perspective, the challenge lies in distinguishing it from the more common ordinary urticaria. Although both have a significant clinical overlap, certain features may be useful in differentiating the two. Ordinary urticaria is usually itchy, evanescent, asymmetrical and responds to antihistamines, while the rash of autoinflammatory syndromes is asymptomatic, longer lasting, symmetrical and does not respond to antihistamines [Table 1].[6] Other cutaneous features that can point toward autoinflammatory syndrome include a recurrent cellulitis-like eruption, neutrophilic dermatoses-like lesions (such as inflammatory nodules, ulcers or pustules), leukocytoclastic vasculitis-like purpura, and aphthous ulcers.
Table 1: Urticaria versus urticarial rash of autoinflammatory syndrome

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  Classification of Autoinflammatory Syndromes Top

There is no consensus on the classification of autoinflammatory syndromes at present. The initial classifications were based on the clinical phenotypes. With increasing understanding of their pathogenesis, new classification systems are being based on the underlying molecular defects.[7] We feel a classification based on dermatological manifestations, in the context of associated systemic features, may assist clinicians to narrow down their provisional diagnosis and make a more cost-effective use of genetic testing [Table 2].
Table 2: Classification of monogenic autoinflammatory syndromes based on dermatological manifestations

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  Recurrent Urticarial Eruptions and Fevers: Periodic Fever Syndromes Top

Many autoinflammatory syndromes present with recurrent urticarial eruption and fever and have been traditionally referred to as “periodic fever syndromes.” Patients appear completely well inbetween the inflammatory episodes, however, repeated attacks place them at risk of secondary amyloidosis.[1] Although familial  Mediterranean fever More Details (FMF), cryopyrin-associated periodic syndrome (CAPS), TNF-alpha receptor-associated periodic syndrome (TRAPS), and hyperimmunoglobulin D syndrome (HIDS) are considered under the rubric of “periodic fever syndromes,” only HIDS exhibits true periodicity in the fever pattern. Urticarial skin eruption is a prominent feature of CAPS and HIDS. Although not the leading cutaneous manifestation, urticarial rash can be seen in FMF and TRAPS as well. Clinical parameters such as age of onset, fever duration and periodicity, morphology of skin lesions, associated systemic symptoms and pattern of inheritance can help in the differential diagnosis of periodic fever syndromes [Table 3].
Table 3: Approach to the differential diagnosis of periodic fever syndromes

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Cryopyrin-associated periodic syndrome (also known as cryopyrinopathies)

Although originally described as three separate entities, these are now recognized to lie on a continuum: Familial cold autoinflammatory syndrome (FCAS) lies at the mild end, Neonate-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous and articular syndrome (CINCA) is the most severe form, while Muckle–Wells syndrome (MWS) lies in between. The genetic defect has been characterized as a gain-of-function mutation in the NLRP3 gene coding for the inflammasome cryopyrin.[8]

The most common presentation is as an urticarial eruption starting as early as few hours of birth [Figure 1], with most patients presenting before 6 months of age. Fevers are typically provoked by cold exposure, for example undressing or bathing. Fever occurs for less than a day in FCAS, 1–3 days in MWS, and daily in CINCA. Apart from urticarial skin lesions and fever, patients with FCAS also have joint pains, those with MWS have additional features of hearing loss and ocular inflammation, and those with CINCA have chronic meningitis, developmental delay and joint contractures as well. Patients with MWS and CINCA are at an increased risk of amyloidosis.[9]
Figure 1: Cryopyrin-associated periodic syndrome: Erythematous urticarial plaques, some of which appear annular, on the face and trunk of a 18-month-old girl (Courtesy: Prof. Sandipan Dhar, Institute of Child Health, Kolkata, India)

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Another autoinflammatory syndrome with cold-induced urticarial lesions is the recently described phospholipase Cϒ2-associated antibody deficiency and immune dysregulation. Patients start developing urticarial lesions on cold exposure from infancy, are at risk of recurrent sinopulmonary infections and have autoimmune conditions such as vitiligo, autoimmune thyroiditis and circulating autoantibodies. A subset of these patients develops a vesicular eruption at cold-exposed acral sites during the first few days of life, which gets replaced by granulomatous skin lesions later.[10]

Hyperimmunoglobulin D syndrome (also known as mevalonate kinase deficiency)

Pathogenesis of HIDS is not completely understood and link with inflammasome pathway is unclear. Mutations in the gene coding for mevalonate kinase enzyme have been identified in patients with HIDS.[11]

Disease onset is in early childhood, with mean age of around 6 months. Patients develop recurrent painful urticarial lesions or morbilliform rash, coinciding with fever which lasts for 3–7 days, occurring at regular intervals of 4–8 weeks. Roughly, half the patients also have oral and/or genital aphthae. Other cutaneous lesions include inflammatory nodules, purpura, erythema elevatum diutinum-like lesions, and pseudocellulitis. Characteristic systemic features of HIDS are acute abdominal pain along with vomiting and diarrhea, hepatosplenomegaly, and tender cervical lymphadenopathy.[11],[12]

Periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome is the most common periodic fever syndrome during childhood. Clinical features are similar to HIDS, but the molecular basis has not yet been identified. Like HIDS, the febrile episodes are at fixed intervals, last about a week, and are accompanied by aphthae [Figure 2], sore throat, acute abdomen and lymphadenopathy. However, skin manifestations are rare and most children outgrow the disease by adolescence.[13],[14] An important differential diagnosis of PFAPA syndrome is cyclic neutropenia, also characterized by recurrent fever, oral aphthae, pharyngitis and lymphadenopathy. In addition, patients have intermittent neutropenia (<500/mm3) during febrile episodes which puts them at risk of infection. The gene neutrophil elastase is mutated in cyclic neutropenia.[15]
Figure 2: Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: Oral aphthous ulcer on the inner aspect of upper lip in a 10-year-old boy with recurrent fever and sore throat (Courtesy: Prof. Sandipan Dhar, Institute of Child Health, Kolkata, India)

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Tumour necrosis factor-alpha receptor-associated periodic syndrome

TRAPS was initially named as Familial Hibernian fever because it is more commonly seen in individuals with a Northern European ancestry. The defect lies not in the inflammasome but in the TNF-signalling pathway. The gene coding for TNF-α receptor-1 is mutated, resulting in defective shedding of the receptor from the cell surface.[16]

The age of onset is variable in TRAPS, ranging from neonatal period to fifth decade with the median age being 3 years. The most prominent skin manifestation is a warm, tender centrifugally spreading erythematous plaque which migrates from trunk to extremities, usually on the upper extremities, either quickly over a period of minutes or slowly over several days. Other cutaneous manifestations can include peri-orbital edema, reticulate erythema, urticarial rash and purpura. Patients also have recurrent fever lasting from 7 to 21 days, associated with migratory myalgias (underlying the migratory skin eruption), serositis, and lymphadenopathy.[17],[18]

Familial Mediterranean fever

Perhaps the most common periodic fever syndrome, FMF typically affects patients of Eastern Mediterranean origin. Turkey seems to have the highest prevalence of FMF, with prevalence ranging from 1:400 to 1:1000.[19] The genetic defect has been identified as a loss-of-function mutation in MEFV gene which results in unregulated activation of inflammasome. Mutation M694V is associated with a more severe disease and a higher risk of amyloidosis.[20]

The onset is during childhood or adolescence; about 50% children experience their first attack before their 10th birthday, and >90% have had an episode before the age of 20 years. Erysipelas-like skin eruption or pseudocellulitis is the hallmark cutaneous manifestation but is seen in only about 15%–20% of children. It is typically unilateral and affects the lower limb usually below the knee joint. Other skin lesions include inflammatory nodules and purpura, and rarely urticarial rash. Febrile episodes are short-lasting (6–72 h) and self-limiting. Apart from fever, other systemic symptoms include joint pains and serositis (pleuritic chest pain, peritonitis, orchitis).[21],[22]

  Workup and Treatment: General Principles Top

Typically, markers of systemic inflammation (such as leukocyte count, ferritin, erythrocyte sedimentation rate and C-reactive protein) are raised during the episode and normalize in between the attacks. There may be anemia of chronic disease in long-standing disease. Serology for antinuclear antibody should be done to rule out autoimmune disorders. Histopathological examination from a skin lesion may not be diagnostic of a particular disease, but rather the features vary depending on the clinical morphology: urticarial eruption (perivascular nonspecific chronic and/or neutrophilic inflammatory infiltrate in dermis), purpura (angiocentric neutrophilic infiltrate, erythrocyte extravasation, fibrinoid necrosis of vessel walls), inflammatory nodule (acute inflammatory infiltrate in the dermis which may extend to the panniculus, some may show additional features of vasculitis), or pustule (intra-epidermal neutrophilic collections). More importantly, it helps to exclude other differential diagnoses such as infections and lymphomas. Renal function tests and urine examination for proteinuria should be performed at regular intervals for early detection of renal amyloidosis. Serum amyloid P scintigraphy may be done where facilities are available. Raised immunoglobulin levels can be a nonspecific finding, although two documented IgD levels >100 mg/L at least 1 month apart with a consistent clinical presentation can suggest the diagnosis of HIDS.[23] Specific diagnosis rests on genetic analysis. However, it is important to remember that a negative result on genetic testing does not exclude the diagnosis: sensitivity of testing a single gene is quite low owing to a large degree of phenotypic overlap between different autoinflammatory syndromes and further, molecular basis of several autoinflammatory syndromes is not known yet.

Traditionally, systemic corticosteroids and other anti-inflammatory agents have been used to treat the inflammatory episodes with variable results. Colchicine has been effective, but primarily in the treatment of FMF. Recent advances in our understanding of the molecular basis of these disorders have allowed us to use novel biological treatments targeting the dysregulated inflammasome/IL-1 pathway with great success. Anti-IL-1 treatments (anakinra, rilonacept and canakinumab) have been effective in the treatment of many autoinflammatory syndromes but have to be given at regular intervals.[24] So good is the response to anakinra that it may also be used as a therapeutic trial when the diagnosis is in doubt.[25] Apart from anti-IL-1 therapy, TNF-α blockers have also been tried but with mixed results. It is important that these patients are managed in consultation with pediatricians or physicians experienced with these rare diseases.

  Other Autoinflammatory Syndromes not Characterized by Periodic Fevers Top

The clinical spectrum of monogenic autoinflammatory syndromes is extending beyond periodic fever syndromes and newer disorders are now being recognized which do not have recurrent fever.[26],[27] A detailed discussion of all the newer entities is beyond the scope of this review. Some, having distinctive cutaneous features, are discussed briefly below.

Neutrophilic skin lesions

Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) and Pyoderma gangrenosum, acne and suppurative hidradenitis (PASH) syndromes are characterized by pyoderma gangrenosum-like ulcers during childhood and severe acne at puberty.[28],[29] In addition, patients with PAPA syndrome have recurrent sterile monoarthritis and those with PASH suffer from hidradenitis suppurativa.[30] PAPA syndrome has an autosomal dominant mode of transmission; the genetic defect is a mutation in PSTPIP1/CD2BP1 gene which results in increased binding of pyrin to NLRP leading to inflammasome formation.[31] The genetic basis of PASH syndrome is not yet known. Some autoinflammatory syndromes such as deficiency of IL-1 receptor antagonist (DIRA) and deficiency of IL-36 receptor antagonist (DITRA) present during infancy with recurrent crops of generalized pustular eruption resembling pustular psoriasis. Both DIRA and DITRA have an autosomal recessive inheritance. DIRA also has periostitis, multifocal osteomyelitis, dystrophic nails, and respiratory distress due to progressive interstitial fibrosis.[32] DITRA lacks the systemic features of DIRA but has fever which is typically absent in DIRA.[33]

Granulomatous skin lesions

Blau syndrome (also known as neonatal-onset sarcoidosis) is characterized by the triad of granulomatous skin lesions, symmetric polyarthritis with boggy joint swellings and ocular inflammation (uveitis, glaucoma). It has an autosomal-dominant mode of inheritance and occurs due to mutation in CARD-15/NOD-2 gene. The skin lesions appear as generalized monomorphic pin head-sized papules which can become confluent and show noncaseating granulomas on biopsy. Characteristically, skin lesions appear first, usually between 2 and 4 years of age, followed by joint and eye involvement. Fingers and toes can develop flexion contractures later on.[34] Recalcitrant large leg ulcers, which also show granulomas on histopathology, have also been described in some patients.[35],[36]

Panniculitis, lipoatrophy and vasculopathic skin lesions

Some of the more recently described autoinflammatory syndromes are driven by high levels of type I interferon, instead of IL-1, and are thus referred to as interferonopathies. Unlike their IL-1 mediated counterparts which commonly exhibit urticarial and neutrophilic skin lesions, these are characterized by panniculitis, lipoatrophy and vasculopathic lesions and can also have severe neurological manifestations and frequent occurrence of autoantibodies.[37]


Chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature (CANDLE) syndrome occurs due to mutations in PSMB8 gene which leads to impaired proteasome function.[38] A similar disease, by the name of Nakajo–Nishimura syndrome, has been described in Japan.[39] Children present within the first few years of life with daily high-grade fevers, joint and muscle pains, erythematous-violaceous nodules and annular plaques on trunk and extremities, erythematous swelling of the eyelids, lipoatrophy, metabolic syndrome, and delayed physical development. Skin biopsy characteristically shows mature neutrophils and atypical mononuclear infiltrates of myeloid lineage.[38],[40] Many clinical features, such as myalgias, heliotrope-like rash, lipoatrophy, and metabolic syndrome, can resemble those of juvenile dermatomyositis.

Although not an interferonopathy, a mention of H-syndrome is made here because of its peculiar panniculitic skin lesions: hyperpigmented, hypertrichotic, indurated, warm, and tender plaques present symmetrically on the lower trunk and lower extremities appearing during the first or second decade of life [Figure 3]. Other manifestations include hyperglycemia, short height, hearing loss, hepatosplenomegaly, hallux valgus and joint contractures, and cardiac defects.[41] Mutations in gene SLC29A3 encoding for a nucleoside transporter have been identified, which result in macrophage dysfunction explaining the dermal and subcutaneous histiocytic infiltrates seen on skin biopsy.[42],[43]
Figure 3: H-syndrome: Symmetrical hyperpigmented hypertrichotic indurated plaques present on bilateral thighs and legs, with sparing of knees

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On the other hand, stimulator of interferon genes associated vasculopathy with onset in infancy (SAVI) and Aicardi–Goutieres syndrome (AGS) are characterized by childhood-onset of chilblain-like vasculopathic acral (on fingers, toes, ears, nose tip, and cheeks) lesions aggravated by cold exposure, which heal with necrosis and scarring.[44],[45],[46] Patients with AGS can experience other cold-related problems as well, such as acrocyanosis and livedo reticularis. The extracutaneous features differ between these two disorders: fever and interstitial lung disease in SAVI,[44] while prominent neurological features such as early-onset encephalopathy, lymphocytic meningitis, microcephaly, developmental delay, strokes, dystonia, and intracranial calcifications in AGS.[47] Deficiency of adenosine deaminase-2 is another autoinflammatory syndrome with vasculopathic manifestations: Raynaud's phenomenon, livedo reticularis, inflammatory nodules, purpura and leg ulcers. Other features include fever, early-onset and recurrent strokes, peripheral neuropathy, and hepatosplenomegaly.[48]

  Conclusion Top

Skin lesions can be the leading clinical symptoms and are often one of the earliest presentations of autoinflammatory syndromes. Further, systemic features are largely nonspecific and do not add to the differential diagnosis. It is therefore imperative that the dermatologists are aware of the cutaneous manifestations as their input can be invaluable in making the correct diagnosis and initiating early treatment.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]

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